Aida Habtezion MD MSc.

All Publications

• Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages. Gastro hep advances Bishop, E. S., Namkoong, H., Aurelian, L., McCarthy, M., Nallagatla, P., Zhou, W., Neshatian, L., Gurland, B., Habtezion, A., Becker, L. 2023; 2 (2): 261-276

  Abstract

  Muscularis macrophages (MMs) are tissue-resident macrophages in the gut muscularis externa which play a supportive role to the enteric nervous system. We have previously shown that age-dependent MM alterations drive low-grade enteric nervous system inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline.Young (3 months) and old (16-24 months) C57BL/6 mice and human tissue were studied. Immune cells from mouse small intestine, colon, and spinal cord and human colon were dissociated, immunophenotyped by flow cytometry, and examined for gene expression by single-cell RNA sequencing and quantitative real-time PCR. Phagocytosis was assessed by in vivo injections of pHrodo beads (Invitrogen). Macrophage counts were performed by immunostaining of muscularis whole mounts.MMs from young and old mice express homeostatic microglial genes, including Gpr34, C1qc, Trem2, and P2ry12. An MM subpopulation that becomes more abundant with age assumes a geriatric state (GS) phenotype characterized by increased expression of disease-associated microglia genes including Cd9, Clec7a, Itgax (CD11c), Bhlhe40, Lgals3, IL-1β, and Trem2 and diminished phagocytic activity. Acquisition of the GS phenotype is associated with clearance of α-synuclein aggregates. Human MMs demonstrate a similar age-dependent acquisition of the GS phenotype associated with intracellular α-synuclein accumulation.MMs demonstrate age-dependent genetic changes that mirror the microglial disease-associated microglia phenotype and result in functional decline.

  View details for DOI 10.1016/j.gastha.2022.09.006

  View details for PubMedID 36908772

  View details for PubMedCentralID PMC10003669

• Mass-cytometry-based quantitation of global histone post-translational modifications at single-cell resolution across peripheral immune cells in IBD. Journal of Crohn's & colitis Bai, L., Dermadi, D., Kalesinskas, L., Dvorak, M., Chang, S. E., Ganesan, A., Rubin, S. J., Kuo, A., Cheung, P., Donato, M., Utz, P. J., Habtezion, A., Khatri, P. 2022

  Abstract

  Current understanding of histone post-translational modifications (histone modifications) across immune cell types in patients with inflammatory bowel disease (IBD) during remission and flare is limited. The study aimed to quantify histone modifications at a single-cell resolution in IBD patients during remission and flare and how they differ compared to healthy controls.We performed a case-control study of 94 subjects (83 IBD patients and 11 healthy controls). IBD patients had either UC (n=38) or CD (n=45) in clinical remission or flare. We used epigenetic profiling by time-of-flight (EpiTOF) to investigate changes in histone modifications within peripheral blood mononuclear cells from IBD patients.We discovered substantial heterogeneity in histone modifications across multiple immune cell types in IBD patients. They had a higher proportion of less differentiated CD34 + hematopoietic progenitors, and a subset of CD56 bright NK cells and γδ T cells characterized by distinct histone modifications associated with the gene transcription. The subset of CD56 bright NK cells had increased several histone acetylations. An epigenetically defined subset of NK was associated with higher levels of CRP in peripheral blood. CD14+ monocytes from IBD patients had significantly decreased cleaved H3T22, suggesting they were epigenetically primed for macrophage differentiation.We describe the first systems-level quantification of histone modifications across immune cells from IBD patients at a single-cell resolution revealing the increased epigenetic heterogeneity that is not possible with traditional ChIP-seq profiling. Our data open new directions in investigating the association between histone modifications and IBD pathology using other epigenomic tools.

  View details for DOI 10.1093/ecco-jcc/jjac194

  View details for PubMedID 36571819

• Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival. World journal of gastroenterology Weingarden, A. R., Gubatan, J., Singh, S., Balabanis, T. C., Patel, A., Sharma, A., Habtezion, A. 2022; 28 (39): 5750-5763

  Abstract

  Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients.To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC.IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07).IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.

  View details for DOI 10.3748/wjg.v28.i39.5750

  View details for PubMedID 36338892

  View details for PubMedCentralID PMC9627421

• Salivary Biomarker Evaluation of Chronic Pancreatitis Patients Reveals Alterations in Human Proteins, Cytokines, Prostaglandin E2 Levels, and Bacterial Diversity. Pancreas Waldron, R. T., Jones, E. K., Anani, V. I., Hines, J. M., Zhao, J., Lugea, A., Diniz, M. A., Kim, S., Habtezion, A., Hoffman, K. L., Petrosino, J. F., Fisher, W. E., Li, L., Lennon, R. J., Singh, R. J., Vege, S. S., Pandol, S. J., Topazian, M. D. 2022; 51 (7): 723-732

  Abstract

  OBJECTIVES: Chronic pancreatitis (CP) is a chronic fibroinflammatory condition of the pancreas difficult to diagnose in early stages. Novel biomarkers useful to facilitate early diagnosis or treatment responses may be found in biofluids. Although saliva can be easily and noninvasively collected from patients, useful salivary biomarkers from CP patients have not yet been identified.METHODS: Here, we analyzed the proteome by quantitative proteomics, cytokine/chemokine levels by Luminex analysis, prostaglandin E2 (PGE2) levels by a mass spectrometry-based assay, and bacterial species diversity by 16S ribosomal ribonucleic acid sequencing in saliva samples from confirmed CP patients and healthy controls.RESULTS: Our results indicate the presence of various differentially expressed proteins, cytokines/chemokines, and a loss of oral bacterial diversity in the saliva of CP patients. The PGE2 levels trend toward elevation in CP patients. Area under the receiver operating characteristic curve models for proteomic, cytokine, and PGE2 assays ranged from 0.59 to 0.90.CONCLUSIONS: Collectively, our studies identify a range of putative CP biomarkers and alterations in human saliva requiring further validation. The biomarker discovery approaches we used might lead to identification of biomarkers useful for CP diagnosis and monitoring.

  View details for DOI 10.1097/MPA.0000000000002113

  View details for PubMedID 36395395

• 2022 American Pancreatic Association Presidential Address: Resilience. Pancreas Habtezion, A. 2022; 51 (7): 713-714

  View details for DOI 10.1097/MPA.0000000000002094

  View details for PubMedID 36395393

• p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases. Cancer communications (London, England) Fajardo, P., Taskova, M., Martín-Serrano, M. A., Hansen, J., Slott, S., Jakobsen, A. K., Wibom, M. L., Salegi, B., Muñoz, A., Barbachano, A., Sharma, A., Gubatan, J. M., Habtezion, A., Sanz-Ezquerro, J. J., Astakhova, K., Cuenda, A. 2022

  View details for DOI 10.1002/cac2.12331

  View details for PubMedID 35796643

• A tissue-like neurotransmitter sensor for the brain and gut. Nature Li, J., Liu, Y., Yuan, L., Zhang, B., Bishop, E. S., Wang, K., Tang, J., Zheng, Y., Xu, W., Niu, S., Beker, L., Li, T. L., Chen, G., Diyaolu, M., Thomas, A., Mottini, V., Tok, J. B., Dunn, J. C., Cui, B., Pașca, S. P., Cui, Y., Habtezion, A., Chen, X., Bao, Z. 2022; 606 (7912): 94-101

  Abstract

  Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract1-3. Their real-time monitoring will offer critical information for understanding neural function and diagnosing disease1-3. However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, especially in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examining soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochemical biological interface termed NeuroString, which is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomolecular sensing in other soft organs across the body.

  View details for DOI 10.1038/s41586-022-04615-2

  View details for PubMedID 35650358

• Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRalpha+ Cells Is a New Marker for Inflammatory Bowel Disease. International journal of molecular sciences Ha, S. E., Jorgensen, B. G., Wei, L., Jin, B., Kim, M., Poudrier, S. M., Singh, R., Bartlett, A., Zogg, H., Kim, S., Baek, G., Kurahashi, M., Lee, M., Kim, Y., Choi, S., Sasse, K. C., Rubin, S. J., Gottfried-Blackmore, A., Becker, L., Habtezion, A., Sanders, K. M., Ro, S. 2022; 23 (9)

  Abstract

  Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRalpha+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRalpha+ cells. ADAMDEC1 protein was mainly released from PDGFRalpha+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRalpha+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRalpha+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRalpha+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRalpha+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

  View details for DOI 10.3390/ijms23095007

  View details for PubMedID 35563399

• The effect of gastric acid suppression on probiotic colonization in a double blinded randomized clinical trial. Clinical nutrition ESPEN Singh, G., Haileselassie, Y., Briscoe, L., Bai, L., Patel, A., Sanjines, E., Hendler, S., Singh, P. K., Garud, N. R., Limketkai, B. N., Habtezion, A. 1800; 47: 70-77

  Abstract

  BACKGROUND & AIMS: Probiotics contain living microorganisms consumed for their putative benefits on the intestinal microbiota and general health and a concept is emerging to use probiotic as a therapeutic intervention to reduce proton pump inhibitors (PPIs) negative effects, but data is lacking. The use of PPIs can result in disordered gut microbiota, leading to a risk of enteric infections. PPIs are frequently prescribed in the general practice setting for gastroesophageal reflux disease (GERD), peptic ulcer disease, and related conditions. Despite the availability and widespread use of probiotics and acid-suppressing medications, the effect of PPIs-induced gastric acid suppression on the survival and colonization of probiotics bacterial species is currently unclear. We hypothesized that gastric acid suppression may improve intestinal colonization of probiotics bacterial species and probiotic intervention may have a potential role in mitigating untoward effects of PPI.METHODS: In a randomized, double-blind, placebo-controlled study, healthy subjects were given either proton pump inhibitor (PPI, n=15) or placebo (n=15) over 6 weeks. All subjects then consumed multi-strain probiotics from weeks 2-6. Thirty participants (10 males, 20 females, age range: 18-56 years) were enrolled in the study. Shotgun metagenomic sequencing and untargeted metabolomics analyses were performed on stool samples collected at week 0, 2, and 6.RESULTS: Short term PPI treatment increased the microbial abundance of Streptococcaceae (p=0.004), Leuconostacaceae (p=0.001), and Pasteurellaceae (p=0.020) at family level and corresponding genus levels. The metabolomic analysis of the stools revealed a change in 10 metabolites where Gly Arg Val and phenylacetic acid were consistently increased compared to the baseline. Probiotic intervention inhibited PPI-induced microbial changes such as a decrease in Leuconostacaceae family (p=0.01) and led to an increase in metabolite 1H-Indole-4-carbaldehyde. Notably, PPI enhanced the colonization of certain probiotic bacterial species like Streptococcus thermophilus (p<0.05) along with other species present in the multi-strain probiotic.CONCLUSION: Acid suppression enhanced certain probiotic associated bacterial colonization and probiotics in turn suppressed PPI-mediated intestinal microbial alterations. Thus, probiotics in combination with PPI might be a beneficial strategy that allows probiotic colonization and suppress PPI-induced microbial perturbations. CLINICAL TRIALS.GOV, NUMBER: NCT03327051.

  View details for DOI 10.1016/j.clnesp.2021.11.005

  View details for PubMedID 35063245

• Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy. World journal of clinical cases Rubin, S. J., Balabanis, T., Gubatan, J., Habtezion, A. 2022; 10 (6): 1787-1794

  Abstract

  Colitis is a known potential toxicity of immune checkpoint inhibitors (ICIs). Studies evaluating the risk of disease exacerbation following ICI treatment in patients with pre-existing inflammatory bowel disease (IBD) are limited.To assess the clinical characteristics of IBD patients treated with ICIs and determine prevalence of subsequent IBD exacerbations.We conducted a retrospective cohort study of all patients in the Stanford Research Repository database with pre-existing IBD who were exposed to ICIs.The prevalence of IBD exacerbation following ICI was 36.8% amongst 19 patients meeting inclusion criteria. Patients with exacerbations had more gastrointestinal-related hospitalizations (4 of 7) than patients without exacerbations (0 of 12; P = 0.0090).The prevalence of IBD exacerbations following ICI was higher than reported rates of ICI-induced colitis and diarrhea in the general population and was associated with hospitalization.

  View details for DOI 10.12998/wjcc.v10.i6.1787

  View details for PubMedID 35317167

  View details for PubMedCentralID PMC8891792

• Randomized, Double-Blinded, Placebo-Controlled Trial of Simvastatin to Prevent Recurrent Pancreatitis PANCREAS Goodman, M. T., Lo, S. K., Yadav, D., Wu, B. U., Jamil, L. H., Kwok, K. K., Papachristou, G. I., Afghani, E., Choi-Kuaea, Y., Waldron, R. T., Lombardi, C., Jeon, C. Y., Helenowski, I. B., Richmond, E., Benante, K., Habtezion, A., Schering, T., Khan, S. A., Rodriguez, L. M., Pandol, S. J. 2022; 51 (1): E10-E12

  View details for Web of Science ID 000759723600009

  View details for PubMedID 35195610

  View details for PubMedCentralID PMC8887796

• Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis. Gut Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G. L., Davis, M. M., Husain, S. Z., Pandol, S. J., Bellin, M. D., Habtezion, A. 2021

  Abstract

  OBJECTIVE: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.DESIGN: We performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort.RESULTS: Deep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay.CONCLUSION: Single-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

  View details for DOI 10.1136/gutjnl-2021-324546

  View details for PubMedID 34702715

• Immune Checkpoint Inhibitor-Mediated Colitis Is Associated With Improved Cancer Overall Survival Weingarden, A. R., Gubatan, J., Balabanis, T., Patel, A., Singh, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: S1381

  View details for Web of Science ID 000717526105475

• Computational drug repositioning of atorvastatin for ulcerative colitis. Journal of the American Medical Informatics Association : JAMIA Bai, L., Scott, M. K., Steinberg, E., Kalesinskas, L., Habtezion, A., Shah, N. H., Khatri, P. 2021

  Abstract

  OBJECTIVE: Ulcerative colitis (UC) is a chronic inflammatory disorder with limited effective therapeutic options for long-term treatment and disease maintenance. We hypothesized that a multi-cohort analysis of independent cohorts representing real-world heterogeneity of UC would identify a robust transcriptomic signature to improve identification of FDA-approved drugs that can be repurposed to treat patients with UC.MATERIALS AND METHODS: We performed a multi-cohort analysis of 272 colon biopsy transcriptome samples across 11 publicly available datasets to identify a robust UC disease gene signature. We compared the gene signature to in vitro transcriptomic profiles induced by 781 FDA-approved drugs to identify potential drug targets. We used a retrospective cohort study design modeled after a target trial to evaluate the protective effect of predicted drugs on colectomy risk in patients with UC from the Stanford Research Repository (STARR) database and Optum Clinformatics DataMart.RESULTS: Atorvastatin treatment had the highest inverse-correlation with the UC gene signature among non-oncolytic FDA-approved therapies. In both STARR (n = 827) and Optum (n = 7821), atorvastatin intake was significantly associated with a decreased risk of colectomy, a marker of treatment-refractory disease, compared to patients prescribed a comparator drug (STARR: HR = 0.47, P = .03; Optum: HR = 0.66, P = .03), irrespective of age and length of atorvastatin treatment.DISCUSSION & CONCLUSION: These findings suggest that atorvastatin may serve as a novel therapeutic option for ameliorating disease in patients with UC. Importantly, we provide a systematic framework for integrating publicly available heterogeneous molecular data with clinical data at a large scale to repurpose existing FDA-approved drugs for a wide range of human diseases.

  View details for DOI 10.1093/jamia/ocab165

  View details for PubMedID 34529084

• Muscularis macrophages express microglial genes and develop a DAM-like phenotype in aging Bishop, E., Zhou, W., Habtezion, A., Becker, L. WILEY. 2021

  View details for Web of Science ID 000704860100034

• Novel circulating and tissue monocytes as well as macrophages in pancreatitis and recovery. Gastroenterology Manohar, M., Jones, E. K., Rubin, S. J., Subrahmanyam, P. B., Swaminathan, G., Mikhail, D., Bai, L., Singh, G., Wei, Y., Sharma, V., Siebert, J. C., Maecker, H. T., Husain, S. Z., Park, W. G., Pandol, S. J., Habtezion, A. 2021

  Abstract

  BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies.METHODS: We performed single-cell mass cytometry (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild (referred as AP), severe AP (SAP) and recovery using two independent experimental models and blood from AP and recurrent AP (RAP) patients. Flowcytometric validation of monocytes subsets identified by CyTOF analysis was performed independently.RESULTS: Ly6C+ inflammatory monocytes were most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified seven novel subsets during AP and recovery, and six monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified seven novel subsets during AP, recovery and SAP. DE analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, PDPN) and functional markers (IFN-gamma, IL-4, IL-22, LAP-TGF-beta, TNF-alpha, T-bet, RoRgammat) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and RAP.CONCLUSION: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

  View details for DOI 10.1053/j.gastro.2021.08.033

  View details for PubMedID 34450180

• Association of Longitudinal Changes in Skeletal Muscle Mass With Survival in Patients With Pancreatic Cancer Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G., Davis, M., Pandol, S. J., Bellin, M. D., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1073

  View details for Web of Science ID 000706786400146

• Novel Circulating and Tissue Monocytes As Well As Macrophages in Pancreatitis and Recovery Manohar, M., Jones, E. K., Rubin, S. S., Subrahmanyam, P. B., Mikhail, D., Bai, L., Singh, G., Wei, Y., Sharma, V., Swaminathan, G., Siebert, J. C., Maecker, H. T., Park, W., Pandol, S. J., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1079-1080

  View details for Web of Science ID 000706786400172

• Immune Profiling Human Pancreatitis Jones, E. K., Holmes, T., Lee, B., Manohar, M., Li, L., Yadav, D., Conwell, D. L., Park, W. G., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1068-1069

  View details for Web of Science ID 000706786400127

• Single-cell Sequencing Unveils Distinct Immune Microenvironment in Human Chronic Pancreatitis Lee, B., Namkoong, H., Yang, Y., Huang, H., Heller, D., Szot, G., Davis, M., Pandol, S. J., Bellin, M. D., Husain, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: 1073

  View details for Web of Science ID 000706786400147

• Protective Effect of Saffron in Mouse Colitis Models Through Immune Modulation. Digestive diseases and sciences Singh, G., Haileselassie, Y., Ji, A. R., Maecker, H. T., Sinha, S. R., Brim, H., Habtezion, A., Ashktorab, H. 2021

  Abstract

  BACKGROUND: People with inflammatory bowel disease (IBD) including ulcerative colitis are at risk for colorectal cancer. Despite available effective drugs used to treat IBD, many patients fail or lose response over time with some displaying drug-induced adverse events. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD has not been explored extensively.AIM: To establish whether saffron treatment alleviates inflammation in experimental colitis.METHODS: Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron doses (7.5, 15, 20, 25mg/kg body weight) or vehicle through daily gavage. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for mRNA and protein expression of HO-1 protein and GPX2, (the downstream targets of NRF-2). Nrf-2 translocation from cytosol to nucleus was confirmed by immunofluorescence, and further Nrf-2 protein expression in nuclear and cytosolic fraction of colon was analyzed by immunoblot. Immune cells were isolated from the lamina propria of mouse colon for flow cytometry-based immunophenotyping. Colitis was also induced in C57BL/6 Ahr knockout and wild type mice to explore the involvement of Ahr-dependent pathways in saffron's protective effect(s). The therapeutic effect of saffron was further validated in another TNBS model of colitis.RESULTS: Saffron 20mg/kg body weightshowed improved colon gross and histology features and led to better body weight, colon length, histology score, and reduced disease activity index (DAI). Saffron significantly decreased pro-inflammatory macrophages (M1), while increasing anti-inflammatory macrophages (M2) and IL10+dendritic cells. Saffron treatment also enhanced CD3+T and CD3+CD8+T cells followed by increase in different CD3+CD4+T cells subsets like CD25+T cells, FoxP3+CD25+regulatory T cells, and CD4+FOXP3+CD25-regulatory T cells. Immunoblot analysis showed a significant increase in HO-1/GPX2 protein expression. With saffron treatment, Nrf-2 translocation into nucleus from cytosol also supports the involvement of Nrf-2 and its downstream targets in the protective effect of saffron. Further, we demonstrated that saffron in part exert anti-inflammatory effect through activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways.CONCLUSION: These data demonstrate saffron's therapeutic potential and its protective role in part via Ahr/Nrf-2 pathways and regulatory innate and adaptive immune cells.

  View details for DOI 10.1007/s10620-021-07163-3

  View details for PubMedID 34275090

• CYTOKINE PROFILE ELEVATIONS ON ADMISSION CAN DETERMINE RISKS OF SEVERE ACUTE PANCREATITIS IN CHILDREN. The Journal of pediatrics Farrell, P. R., Jones, E. K., Hornung, L., Thompson, T., Patel, J., Lin, T. K., Nathan, J. D., Vitale, D. S., Habtezion, A., Abu-El-Haija, M. 2021

  Abstract

  OBJECTIVES: To utilize a Luminex platform to examine multiple cytokines simultaneously as well as clinical laboratory testing in order to identify markers that predict acute pancreatitis (AP) severity in the pediatric population on admission.STUDY DESIGN: Patients (<19 years) prospectively enrolled over a 4-year period in a single institution AP database were included in separate derivation and validation cohorts. Plasma samples were obtained within 48 hours of admission and stored for analysis. Samples from mild AP and SAP (moderately severe and severe combined) were analyzed using Luminex panels and C-Reactive Protein (CRP) testing.RESULTS: The derivation cohort examined 62 cytokines in 66 subject samples (20 control, 36 mild AP, 10 SAP) and identified interleukin 6 (IL-6) [P = .02] and monocyte chemotactic protein-1 (MCP-1) [p=0.02] as cytokines that were differentially expressed between mild and SAP. Our validation cohort analyzed 76 cytokines between 10 controls, 19 mild AP and 6 SAP subjects. IL-6 (p=0.02) and MCP-1 (p=0.007) were again found to differentiate mild AP from SAP. CRP values were obtained from 53 of the subjects, revealing a strong association between elevated CRP values and progression to severe disease (P<0.0001).CONCLUSION: This study identified and validated IL-6 and MCP-1 as predictors of SAP using 2 distinct cohorts, and showed that CRP elevation is a marker of progression to SAP. These biomarkers have not been extensively studied in the pediatric AP population. Our data allows for risk-stratification of AP patients, and represent novel insight into the immunologic response in SAP.

  View details for DOI 10.1016/j.jpeds.2021.07.015

  View details for PubMedID 34273357

• Preventive effects of saffron in a colitis mouse model. Banskota, S., Khan, W., Singh, G., Habtezion, A., Brim, H., Ashktorab, H. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263503151

• Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer. Stem cell reports Ouyang, X., Liu, Y., Zhou, Y., Guo, J., Wei, T., Liu, C., Lee, B., Chen, B., Zhang, A., Casey, K. M., Wang, L., Kooreman, N. G., Habtezion, A., Engleman, E. G., Wu, J. C. 2021

  Abstract

  Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSC-based cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8+ Tcell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4+ T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of "iPSC-cancer signature genes" and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.

  View details for DOI 10.1016/j.stemcr.2021.04.004

  View details for PubMedID 33961792

• The aryl hydrocarbon receptor regulates expression of mucosal trafficking receptor GPR15. Mucosal immunology Swaminathan, G., Nguyen, L. P., Namkoong, H., Pan, J., Haileselassie, Y., Patel, A., Ji, A. R., Mikhail, D. M., Dinh, T. T., Singh, H., Liao, B., Vazquez-Montesino, L. M., Butcher, E. C., Habtezion, A. 2021

  Abstract

  GPR15 is a chemoattractant receptor that facilitates colon homing of regulatory and effector CD4+ T cells in health and colitis. The molecular mechanisms that control GPR15 expression are not fully known. Here we report the presence of two highly conserved aryl hydrocarbon receptor (AHR) binding sequences in a 3' enhancer of GPR15, leading us to investigate AHR function in regulating GPR15 expression. Using luciferase reporter assays, we show that AHR activation increased GPR15 expression and requires both the AHR binding sites. Consistent with a transcriptional regulatory role, treatment with AHR agonists induce GPR15 expression on human CD4+ T cells. Using AHR-deficient mice, we demonstrate that the lack of AHR signaling drastically reduces GPR15 expression on effector/memory and Foxp3+ CD4+ T cells. In mixed bone marrow chimeras of AHR-deficient and wildtype cells, GPR15 expression was similarly diminished on AHR-deficient CD4+ effector/memory and regulatory T cells in the colon and small intestine. Furthermore, administration of AHR agonists upregulated GPR15 expression on CD4+ effector/memory T cells and increased their homing capability, especially to the colon. Collectively, our studies reveal a novel function of the AHR in regulation of GPR15 expression and increased colon trafficking of CD4+ T cells expressing GPR15.

  View details for DOI 10.1038/s41385-021-00390-x

  View details for PubMedID 33674764

• A protease-activated, near-infrared fluorescent probe for early endoscopic detection of premalignant gastrointestinal lesions. Proceedings of the National Academy of Sciences of the United States of America Yim, J. J., Harmsen, S., Flisikowski, K., Flisikowska, T., Namkoong, H., Garland, M., van den Berg, N. S., Vilches-Moure, J. G., Schnieke, A., Saur, D., Glasl, S., Gorpas, D., Habtezion, A., Ntziachristos, V., Contag, C. H., Gambhir, S. S., Bogyo, M., Rogalla, S. 2021; 118 (1)

  Abstract

  Fluorescence imaging is currently being actively developed for surgical guidance; however, it remains underutilized for diagnostic and endoscopic surveillance of incipient colorectal cancer in high-risk patients. Here we demonstrate the utility and potential for clinical translation of a fluorescently labeled cathepsin-activated chemical probe to highlight gastrointestinal lesions. This probe stays optically dark until it is activated by proteases produced by tumor-associated macrophages and accumulates within the lesions, enabling their detection using an endoscope outfitted with a fluorescence detector. We evaluated the probe in multiple murine models and a human-scale porcine model of gastrointestinal carcinogenesis. The probe provides fluorescence-guided surveillance of gastrointestinal lesions and augments histopathological analysis by highlighting areas of dysplasia as small as 400 m, which were visibly discernible with significant tumor-to-background ratios, even in tissues with a background of severe inflammation and ulceration. Given these results, we anticipate that this probe will enable sensitive fluorescence-guided biopsies, even in the presence of highly inflamed colorectal tissue, which will improve early diagnosis to prevent gastrointestinal cancers.

  View details for DOI 10.1073/pnas.2008072118

  View details for PubMedID 33443161

• Serotonin is elevated in COVID-19-associated diarrhoea. Gut Ha, S., Jin, B., Clemmensen, B., Park, P., Mahboob, S., Gladwill, V., Lovely, F. M., Gottfried-Blackmore, A., Habtezion, A., Verma, S., Ro, S. 2021

  View details for DOI 10.1136/gutjnl-2020-323542

  View details for PubMedID 33402416

• Reply to Letter to the Editor: What is the incidence of COVID-19 in patients with IBD in western countries? Gastroenterology Gubatan, J. n., Sinha, S. R., Habtezion, A. n. 2021

  View details for DOI 10.1053/j.gastro.2021.01.014

  View details for PubMedID 33453234

• Vitamin D is Associated with α4β7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease. Journal of Crohn's & colitis Gubatan, J., Rubin, S. J., Bai, L., Haileselassie, Y., Levitte, S., Balabanis, T., Patel, A., Sharma, A., Sinha, S. R., Habtezion, A. 2021

  Abstract

  Vitamin D downregulates the in vitro expression of the gut-tropic integrin α4β7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease (IBD) is unclear. We tested the hypothesis that vitamin D is associated with α4β7 immunophenotypes and risk of vedolizumab (anti- α4β7) failure in IBD.We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry (CyTOF) in vedolizumab-naïve patients with IBD (N=48). We analyzed whole-genome mucosal gene expression (GSE73661) from GEMINI I and GEMINI long-term safety (LTS) to determine the association between vitamin D receptor (VDR) and integrin alpha-4 (ITGA4) and beta-7 (ITGB7) genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort (N= 252) with logistic regression.Immunophenotyping revealed that higher 25(OH)D was associated with decreased α4β7+ peripheral blood mononuclear cells (R = -0.400, P < 0.01) and α4β7+ intestinal leukocytes (R = -0.538, P= 0.03). Serum 25(OH)D was inversely associated with α4β7+ peripheral B cells and natural killer (NK) cells and α4β7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25(OH)D < 25 ng/mL was associated with increased vedolizumab primary non-response during induction (OR 26.10, 95% CI 14.30-48.90, P<0.001) and failure at 1-year follow-up (OR 6.10, 95% CI 3.06-12.17, P<0.001).Low serum 25(OH)D is associated with α4β7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD.

  View details for DOI 10.1093/ecco-jcc/jjab114

  View details for PubMedID 34180967

• Gastrointestinal symptoms and healthcare utilization have increased among patients with functional gastrointestinal and motility disorders during the COVID-19 pandemic. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society Gubatan, J., Zikos, T., Spear Bishop, E., Wu, J., Gottfried, A., Becker, L., Habtezion, A., Neshatian, L. 2021: e14243

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented disruptions in healthcare. Functional gastrointestinal and motility disorders (FGIMD) are associated with significant healthcare utilization. The clinical implications of these healthcare disruptions due to the COVID-19 pandemic on clinical outcomes in patients with FGIMD are unclear.We performed a retrospective study of patients with three common FGIMD (irritable bowel syndrome [IBS], gastroparesis, functional dyspepsia [FD]) tested for SARS-CoV-2 to describe alterations in gastrointestinal symptoms, medication use, and healthcare utilization during and before the pandemic and factors associated with COVID-19.The prevalence of COVID-19 during the pandemic (03/2020-09/2020) was 3.20% (83/2592) among patients with FGIMD, 3.62% in IBS (57/1574), 3.07% in gastroparesis (23/749), and 2.44% in FD (29/1187) at our institution. Patients with FGIMD had increased abdominal pain, nausea/vomiting, diarrhea, constipation, and weight loss (p < 0.001) along with increased proton pump inhibitor, H2 blocker, and opioid use (p < 0.0001). Both inpatient hospitalizations and outpatient visits (p < 0.0001) and number of diagnostic tests including cross-sectional imaging (p = 0.002), and upper and lower endoscopies (p < 0.0001) were significantly higher during the pandemic as compared to 6 months prior. Diarrhea-predominant IBS was positively (OR 2.37, 95% CI 1.34-4.19, p = 0.003) associated with COVID-19, whereas functional dyspepsia was negatively (OR 0.46, 95% CI 0.27-0.79, p = 0.004) associated.Patients with common functional gastrointestinal and motility disorders have reported more gastrointestinal symptoms during the COVID-19 pandemic with concurrent increased medication use and healthcare utilization.

  View details for DOI 10.1111/nmo.14243

  View details for PubMedID 34378840

• Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease. Cell reports. Medicine Dai, B., Hackney, J. A., Ichikawa, R., Nguyen, A., Elstrott, J., Orozco, L. D., Sun, K. H., Modrusan, Z., Gogineni, A., Scherl, A., Gubatan, J., Habtezion, A., Deswal, M., Somsouk, M., Faubion, W. A., Chai, A., Sharafali, Z., Hassanali, A., Oh, Y. S., Tole, S., McBride, J., Keir, M. E., Yi, T. 2021; 2 (8): 100381

  Abstract

  Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.

  View details for DOI 10.1016/j.xcrm.2021.100381

  View details for PubMedID 34467254

  View details for PubMedCentralID PMC8385326

• Gastric Mucosal Immune Profiling and Dysregulation in Idiopathic Gastroparesis. Clinical and translational gastroenterology Gottfried-Blackmore, A. n., Namkoong, H. n., Adler, E. n., Martin, B. n., Gubatan, J. n., Fernandez-Becker, N. n., Clarke, J. O., Idoyaga, J. n., Nguyen, L. n., Habtezion, A. n. 2021; 12 (5): e00349

  Abstract

  It is unclear how immune perturbations may influence the pathogenesis of idiopathic gastroparesis, a prevalent functional disorder of the stomach which lacks animal models. Several studies have noted altered immune characteristics in the deep gastric muscle layer associated with gastroparesis, but data are lacking for the mucosal layer, which is endoscopically accessible. We hypothesized that immune dysregulation is present in the gastroduodenal mucosa in idiopathic gastroparesis and that specific immune profiles are associated with gastroparesis clinical parameters.In this cross-sectional prospective case-control study, routine endoscopic biopsies were used for comprehensive immune profiling by flow cytometry, multicytokine array, and gene expression in 3 segments of the stomach and the duodenal bulb. Associations of immune endpoints with clinical parameters of gastroparesis were also explored.The gastric mucosa displayed large regional variation of distinct immune profiles. Furthermore, several-fold increases in innate and adaptive immune cells were found in gastroparesis. Various immune cell types showed positive correlations with duration of disease, proton pump inhibitor dosing, and delayed gastric emptying.This initial observational study showed immune compartmentalization of the human stomach mucosa and significant immune dysregulation at the level of leukocyte infiltration in idiopathic gastroparesis patients that extends to the duodenum. Select immune cells, such as macrophages, may correlate with clinicopathological traits of gastroparesis. This work supports further mucosal studies to advance our understanding of gastroparesis pathophysiology.

  View details for DOI 10.14309/ctg.0000000000000349

  View details for PubMedID 33979305

• Serotonin Deficiency is Associated with Delayed Gastric Emptying. Gastroenterology Wei, L. n., Singh, R. n., Ha, S. E., Martin, A. M., Jones, L. n., Jin, B. n., Jorgenson, B. G., Zogg, H. n., Chervo, T. n., Gottfried-Blackmore, A. n., Nguyen, L. n., Habtezion, A. n., Spencer, N. J., Keating, D. J., Sanders, K. M., Ro, S. n. 2021

  Abstract

  Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine, 5-HT), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiological roles of 5-HT deficiency in gastric motility in mice and humans.We developed an inducible, EC cell-specific Tph1CreERT2/+ mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG).Tph1-tdTom mice revealed EC cells were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate.The Tph1CreERT2/+ mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiological mechanism of 5-HT deficiency in IG.

  View details for DOI 10.1053/j.gastro.2021.02.060

  View details for PubMedID 33662386

• Effects of processing conditions on stability of immune analytes in human blood. Scientific reports Gottfried-Blackmore, A., Rubin, S. J., Bai, L., Aluko, S., Yang, Y., Park, W., Habtezion, A. 2020; 10 (1): 17328

  Abstract

  Minimizing variability in collection and processing of human blood samples for research remains a challenge. Delaying plasma or serum isolation after phlebotomy (processing delay) can cause perturbations of numerous analytes. Thus, a comprehensive understanding of how processing delay affects major endpoints used in human immunology research is necessary. Therefore, we studied how processing delay affects commonly measured cytokines and immune cell populations. We hypothesized that short-term time delays inherent to human research in serum and plasma processing impact commonly studied immunological analytes. Blood from healthy donors was subjected to processing delays commonly encountered in sample collection, and then assayed by 62-plex Luminex panel, 40-parameter mass cytometry panel, and 540,000 transcript expression microarray. Variance for immunological analytes was estimated using each individual's baseline as a control. In general, short-term processing delay led to small changes in plasma and serum cytokines (range-10.8 to 43.5%), markers and frequencies of peripheral blood mononuclear cell phenotypes (range 0.19 to 3.54 fold), and whole blood gene expression (stable for>20K genes)-with several exceptions described herein. Importantly, we built an open-access web application allowing investigators to estimate the degree of variance expected from processing delay for measurements of interest based on the data reported here.

  View details for DOI 10.1038/s41598-020-74274-8

  View details for PubMedID 33060628

• Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis. Gut Barreto, S. G., Habtezion, A., Gukovskaya, A., Lugea, A., Jeon, C., Yadav, D., Hegyi, P., Venglovecz, V., Sutton, R., Pandol, S. J. 2020

  Abstract

  Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.

  View details for DOI 10.1136/gutjnl-2020-322163

  View details for PubMedID 32973069

• Chronic pancreatitis LANCET Beyer, G., Habtezion, A., Werner, J., Lerch, M. M., Mayerle, J. 2020; 396 (10249): 499–512

  View details for Web of Science ID 000561621400020

• Macrophage phenotypic switch orchestrates the inflammation and repair/regeneration following acute pancreatitis injury. EBioMedicine Wu, J., Zhang, L., Shi, J., He, R., Yang, W., Habtezion, A., Niu, N., Lu, P., Xue, J. 2020; 58: 102920

  Abstract

  BACKGROUND: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined.METHOD: Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra-/- mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration.FINDINGS: We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration.INTERPRETATION: Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.

  View details for DOI 10.1016/j.ebiom.2020.102920

  View details for PubMedID 32739869

• Inflammatory polyps occur more frequently in inflammatory bowel disease than other colitis patients. BMC gastroenterology Ashktorab, H., Brim, H., Hassan, S., Nouraie, M., Gebreselassie, A., Laiyemo, A. O., Kibreab, A., Aduli, F., Latella, G., Brant, S. R., Sherif, Z., Habtezion, A. 2020; 20 (1): 170

  Abstract

  BACKGROUND: Colitis is generally considered a risk factor for colon neoplasia. However, not all types of colitis seem to have equal neoplastic transformation potential.AIM: To determine the prevalence of colorectal polyps in a predominantly African American population with inflammatory bowel disease (IBD) and Non-IBD/Non-Infectious Colitis (NIC).METHODS: We retrospectively evaluated medical records of 1060 patients previously identified with colitis at Howard University Hospital, based on ICD-10 code. Among these, 485 patients were included in the study: 70 IBD and 415 NIC based on a thorough review of colonoscopy, pathology and clinical reports. Logistic regression analysis was applied to estimate the risk of polyps in patients with IBD compared to those with NIC after adjusting for age and sex. A subgroup analysis within the IBD group was performed.RESULTS: Of the 485 patients, 415 were NIC and 70 were IBD. Seventy-three percent of the NIC patients and 81% of the IBD patients were African Americans. Forty six percent of IBD and 41% of NIC cases were male. IBD patients were younger than NIC patients (median age of 38years vs. 50, P<0.001). The prevalence of all types of polyps was 15.7 and 8.2% in the IBD and NIC groups, respectively (P=0.045). Among patients with polyps, the prevalence of inflammatory polyps was higher in the IBD group (55%) compared to the NIC group (12%). After adjusting for age, sex and race, odds ratio of inflammatory polyps in IBD patients was 6.0 (P=0.016). Adenoma prevalence was 4.3% (3/70) in IBD patients and 3.9% (16/415) in the NIC patients (p=0.75). The anatomic distribution of lesions and colitis shows that polyps occur predominantly in the colitis field regardless of colitis type. Morepolyps were present in the ulcerative colitispatients when compared to Crohn's diseasepatients (27% vs. 5%, P<0.001) within the IBD group.CONCLUSION: Our study shows that inflammatory polyps are more common in IBD patients when compared to NIC patients. Most polyps were in the same location as the colitis.

  View details for DOI 10.1186/s12876-020-01279-y

  View details for PubMedID 32503428

• Clinical and immunomodulatory effects of transcutaneous vagal nerve stimulation for idiopathic gastroparesis Gottfried-Blackmore, A., Namkoong, H., Adler, E. P., Fernandez-Becker, N., Clarke, J., Habtezion, A., Nguyen, L. WILEY. 2020

  View details for Web of Science ID 000521974900325

• Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitis. The Journal of clinical investigation Lee, B., Adamska, J. Z., Namkoong, H., Bellin, M. D., Wilhelm, J. J., Szot, G. L., Louis, D. M., Davis, M. M., Pandol, S., Habtezion, A. 2020

  Abstract

  Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients that included hereditary and idiopathic CP undergoing total pancreatectomy with islet auto-transplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor beta (TCRbeta) repertoire in CP and controls. TCRbeta-sequencing revealed a significant increase in TCRbeta repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vbeta-Jbeta gene family usage between hereditary and idiopathic CP and a positive correlation of TCRbeta rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreata indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanism of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis providing new insights into immune responses associated with human CP.

  View details for DOI 10.1172/JCI134066

  View details for PubMedID 32053120

• Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell host & microbe Sinha, S. R., Haileselassie, Y., Nguyen, L. P., Tropini, C., Wang, M., Becker, L. S., Sim, D., Jarr, K., Spear, E. T., Singh, G., Namkoong, H., Bittinger, K., Fischbach, M. A., Sonnenburg, J. L., Habtezion, A. 2020

  Abstract

  Secondary bile acids (SBAs) are derived from primary bile acids (PBAs) in a process reliant on biosynthetic capabilities possessed by few microbes. To evaluate the role of BAs in intestinal inflammation, we performed metabolomic, microbiome, metagenomic, and transcriptomic profiling of stool from ileal pouches (surgically created resevoirs) in colectomy-treated patients with ulcerative colitis (UC) versus controls (familial adenomatous polyposis [FAP]). We show that relative to FAP, UC pouches have reduced levels of lithocholic acid and deoxycholic acid (normally the most abundant gut SBAs), genes required to convert PBAs to SBAs, and Ruminococcaceae (one of few taxa known to include SBA-producing bacteria). In three murine colitis models, SBA supplementation reduces intestinal inflammation. This anti-inflammatory effect is in part dependent on the TGR5 bile acid receptor. These data suggest that dysbiosis induces SBA deficiency in inflammatory-prone UC patients, which promotes a pro-inflammatory state within the intestine that may be treated by SBA restoration.

  View details for DOI 10.1016/j.chom.2020.01.021

  View details for PubMedID 32101703

• Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer Frontiers in Oncology Yuan, R., Bhattacharya, N., Kenkel, J. A., Shen, J., DiMaio, M. A., Bagchi, S., Prestwood, T. R., Habtezion, A., Engleman, E. G. 2020; 10: 595892

  Abstract

  Enteric glia are a distinct population of peripheral glial cells in the enteric nervous system that regulate intestinal homeostasis, epithelial barrier integrity, and gut defense. Given these unique attributes, we investigated the impact of enteric glia depletion on tumor development in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice, a classical model of colorectal cancer (CRC). Depleting GFAP+ enteric glia resulted in a profoundly reduced tumor burden in AOM/DSS mice and additionally reduced adenomas in the ApcMin/+ mouse model of familial adenomatous polyposis, suggesting a tumor-promoting role for these cells at an early premalignant stage. This was confirmed in further studies of AOM/DSS mice, as enteric glia depletion did not affect the properties of established malignant tumors but did result in a marked reduction in the development of precancerous dysplastic lesions. Surprisingly, the protective effect of enteric glia depletion was not dependent on modulation of anti-tumor immunity or intestinal inflammation. These findings reveal that GFAP+ enteric glia play a critical pro-tumorigenic role during early CRC development and identify these cells as a potential target for CRC prevention.

  View details for DOI 10.3389/fonc.2020.595892

  View details for PubMedCentralID PMC7691584

• SARS-CoV-2 Testing, Prevalence, and Predictors of COVID-19 in Patients with Inflammatory Bowel Disease in Northern California. Gastroenterology Gubatan, J. n., Levitte, S. n., Balabanis, T. n., Patel, A. n., Sharma, A. n., Habtezion, A. n. 2020

  View details for DOI 10.1053/j.gastro.2020.05.009

  View details for PubMedID 32387541

• Chronic pancreatitis. Lancet (London, England) Beyer, G., Habtezion, A., Werner, J., Lerch, M. M., Mayerle, J. 2020; 396 (10249): 499–512

  Abstract

  Chronic pancreatitis is a multifactorial, fibroinflammatory syndrome in which repetitive episodes of pancreatic inflammation lead to extensive fibrotic tissue replacement, resulting in chronic pain, exocrine and endocrine pancreatic insufficiency, reduced quality of life, and a shorter life expectancy. The incidence and prevalence of chronic pancreatitis is rising and no curative treatment is available. Using novel diagnostic algorithms, definitive chronic pancreatitis can be diagnosed by imaging criteria alone, whereas probable chronic pancreatitis requires clinical features and imaging criteria. Criteria for the diagnosis of early chronic pancreatitis are still under discussion and need prospective validation in clinical trials. Cross-sectional imaging should be used first; endoscopic ultrasound is needed only when CT or MRI are inconclusive or to plan therapeutic interventions. Management of chronic pancreatitis requires an interdisciplinary approach including primary care practitioners, gastroenterologists, surgeons, radiologists, pain specialists, and nutritional therapists. Patients with chronic pancreatitis should be seen at least once a year and re-evaluated for causal risk factors, symptom control, and complications such as malnutrition, pancreatic exocrine insufficiency, and diabetes; refer to a specialised centre if symptoms are poorly controlled or there is risk of deterioration. Scoring systems to monitor disease progression have been developed and validated internationally. Interventional treatments for pain or cholestasis should be done by specialists only, and early discussion of treatment approaches should include all medical disciplines involved in care. Throughout this Seminar, we address research needs such as staging of pancreatitis, aspects of malnutrition and pain, and cancer surveillance, to help improve the care of patients.

  View details for DOI 10.1016/S0140-6736(20)31318-0

  View details for PubMedID 32798493

• Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity. Immunity Fenton, T. M., Jørgensen, P. B., Niss, K. n., Rubin, S. J., Mörbe, U. M., Riis, L. B., Da Silva, C. n., Plumb, A. n., Vandamme, J. n., Jakobsen, H. L., Brunak, S. n., Habtezion, A. n., Nielsen, O. H., Johansson-Lindbom, B. n., Agace, W. W. 2020

  Abstract

  The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.

  View details for DOI 10.1016/j.immuni.2020.02.001

  View details for PubMedID 32160523

• Noninvasive vagal nerve stimulation for gastroenterology pain disorders. Pain management Gottfried-Blackmore, A. n., Habtezion, A. n., Nguyen, L. n. 2020

  Abstract

  Abdominal pain continues to be a major challenge and unmet need in clinical practice. Normalization of bidirectional gut-brain signaling has generated much interest as a therapeutic approach to treat chronic abdominal pain. Vagal nerve stimulation (VNS) is emerging as a potential non-pharmacologic strategy for the treatment of abdominal pain. In this review paper, we will summarize the etiologies of chronic pain in gastrointestinal disorders and discuss the rational for VNS as a therapeutic approach to chronic abdominal pain, with particular emphasis in the gammaCore stimulator which allows for noninvasive VNS.

  View details for DOI 10.2217/pmt-2020-0067

  View details for PubMedID 33111642

• Biologics During Pregnancy in Women With Inflammatory Bowel Disease and Risk of Infantile Infections: A Systematic Review and Meta-Analysis. The American journal of gastroenterology Gubatan, J. n., Nielsen, O. H., Levitte, S. n., Juhl, C. B., Maxwell, C. n., Streett, S. E., Habtezion, A. n. 2020

  Abstract

  Biologics, such as tumor necrosis factor inhibitors, anti-integrins and anticytokines, are therapies for inflammatory bowel disease (IBD) that may increase the risk of infection. Most biologics undergo placental transfer during pregnancy and persist at detectable concentrations in exposed infants. Whether this is associated with an increased risk of infantile infections is controversial. We performed a systematic review and meta-analysis evaluating the risk of infantile infections after in utero exposure to biologics used to treat IBD.We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from inception to June 2020 to evaluate the association of biologic therapy during pregnancy in women with IBD and risk of infantile infections. Odds ratios of outcomes were pooled and analyzed using a random effects model.Nine studies met the inclusion criteria comprising 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. Biologic use during pregnancy was not associated with an increased risk of all infantile infections (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.73-1.14, I = 30%). In a subgroup analysis for the type of infection, biologic use was associated with increased infantile upper respiratory infections (OR 1.57, 95% CI 1.02-2.40, I = 4%). Biologic use during pregnancy was not associated with infantile antibiotic use (OR 0.91, 95% CI 0.73-1.14, I = 30%) or infection-related hospitalizations (OR 1.33, 95% CI 0.95-1.86, I = 26%).Biologics use during pregnancy in women with IBD is not associated with the overall risk of infantile infections or serious infections requiring antibiotics or hospitalizations but is associated with an increased risk of upper respiratory infections.

  View details for DOI 10.14309/ajg.0000000000000910

  View details for PubMedID 33110017

• Prevalence, risk factors and clinical outcomes of COVID-19 in patients with a history of pancreatitis in Northern California. Gut Gubatan, J. n., Levitte, S. n., Patel, A. n., Balabanis, T. n., Sharma, A. n., Jones, E. n., Lee, B. n., Manohar, M. n., Swaminathan, G. n., Park, W. n., Habtezion, A. n. 2020

  View details for DOI 10.1136/gutjnl-2020-321772

  View details for PubMedID 32493828

• Elevated Risk for Sessile Serrated Polyps in African Americans with Endometrial Polyps. Digestive diseases and sciences Ashktorab, H., Sherif, Z., Tarjoman, T., Azam, S., Lee, E., Shokrani, B., Okereke, I., Soleimani, A., Carethers, J. M., Laiyemo, A. O., Aduli, F., Nouraie, M., Habtezion, A., Brim, H. 2019

  Abstract

  BACKGROUND: Colorectal and endometrial lesions increase with age. It is not known if these two precursor lesions in sporadic cases associate with each other.AIM: To determine the association between colorectal polyps and endometrial polyps (EP) in African Americans.METHODS: We reviewed records of patients referred to gynecology clinics and had colonoscopy at Howard University Hospital from January 2004 to December 2015. We defined cases as all patients who had EP and underwent colonoscopy. For controls, we used EP-free patients who underwent colonoscopy. Logistic regression analysis was used to assess the association between colon polyps and EP.RESULTS: The median age was 60years in 118 Cases and 57years in 664 Controls. The overall colorectal polyps prevalence in the two groups was not statistically different (54% in controls vs. 52% in cases, P=0.60). Sessile serrated adenoma/polyps (SSPs) were more frequent in cases (8% vs. 2% in controls, P=0.003). Sigmoid and rectal locations were more prevalent in controls than cases. In multivariate analysis and after adjusting for age, diabetes mellitus (DM), and BMI, SSPs were associated with EP occurrence with an odds ratio of 4.6 (CI 1.2-16.7, P=0.022).CONCLUSION: Colorectal polyp prevalence was similar in EP patients compared to EP-free controls. However, we observed a significant association between higher-risk SSPs in patients with EP. The prevalence of smoking and DM was higher in these patients. Females with EP might benefit from a screening for colonic lesions in an age-independent manner.

  View details for DOI 10.1007/s10620-019-05991-y

  View details for PubMedID 31832971

• Open-label pilot study: Non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society Gottfried-Blackmore, A., Adler, E. P., Fernandez-Becker, N., Clarke, J., Habtezion, A., Nguyen, L. 2019: e13769

  Abstract

  BACKGROUND: Gastroparesis, a chronic motility disorder characterized by delayed gastric emptying, abdominal pain, nausea, and vomiting, remains largely unexplained. Medical therapy is limited, reflecting the complex physiology of gastric sensorimotor function. Vagus nerve stimulation is an attractive therapeutic modality for gastroparesis, but prior methods required invasive surgery. In this open-label pilot study, we aimed to assess the benefit of non-invasive vagal nerve stimulation in patients with mild to moderate idiopathic gastroparesis.METHODS: Patients self-administered the gammaCore vagal nerve stimulator for 4weeks. The gastroparesis cardinal symptom index daily diary (GCSI-dd) was assessed during a two-week run-in period, ≥4weeks of therapy, and 4weeks after therapy was completed. Gastric emptying and autonomic function testing were also performed. The primary endpoint was an absolute reduction in CGSI-dd of 0.75 after nVNS.RESULTS: There was a total improvement in symptom scores (2.56±0.76 to 1.87±1.05; P=.01), with 6/15 (40%) participants meeting our primary endpoint. Therapy was associated with a reduction in gastric emptying (T1/2 155 vs 129minutes; P=.053, CI -0.4 to 45). Therapy did not correct autonomic function abnormalities, but was associated with modulation of reflex parasympathetic activity.CONCLUSIONS: Short-term non-invasive vagal nerve stimulation led to improved cardinal symptoms and accelerated gastric emptying in a subset of patients with idiopathic gastroparesis. Responders had more severe gastric delay at baseline and clinical improvement correlated with duration of therapy, but not with improvements in gastric emptying. Larger randomized sham-controlled trials of greater duration are needed to confirm the results of this pilot study.

  View details for DOI 10.1111/nmo.13769

  View details for PubMedID 31802596

• Immune cell signaling in human and mouse pancreas cancer Habtezion, A. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.PANCA19-I10

  View details for Web of Science ID 000526416300149

• Unique circulating immune signatures for recurrent acute pancreatitis, chronic pancreatitis and pancreatic cancer: A pilot study of these conditions with and without diabetes. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] Park, W. G., Li, L., Appana, S., Wei, W., Stello, K., Andersen, D. K., Hughes, S. J., Whitcomb, D. C., Brand, R. E., Yadav, D., Habtezion, A., Consortium for the Study of Chronic Pancreatitis, D. 2019

  Abstract

  OBJECTIVE: This exploratory study seeks to identify distinct circulating immune signatures among patients having recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic adenocarcinoma (PDAC).METHODS: A retrospective analysis of human serum samples from collaborating institutions of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was performed. Samples came from the North American Pancreatitis Studies 2 (NAPS2) cohort and the Pancreatic Adenocarcinoma Gene Environment Risk Study (PAGER) and were analyzed using a 62-plex Luminex assay in a blinded fashion. Group and pairwise comparisons were performed to identify unique immune signature panels and to calculate diagnostic utility using area under the curve analysis.RESULTS: A total of 179 patients' samples were included: 41 controls, 40 CP, 78 PDAC and 20 RAP patients, of which 20 controls, 20 CP, and 58 PDAC patients had diabetes mellitus (DM). A unique immune signature panel could discriminate RAP, CP, and PDAC from controls with an AUC range from 0.77 to 0.86 (95% CI range: 0.64-0.94), RAP from CP, and CP from PDAC with an AUC of 0.77 (95% CI 0.64-0.90) and 0.76 (95% CI 0.67-0.86), respectively. Furthermore, an immune signature panel could also discriminate PDAC-DM from DM controls with an AUC of 0.96 (95% CI: 0.93-1.00) CONCLUSION: This study identifies unique immune analytes that may serve as novel diagnostic and predictive non-invasive biomarkers of RAP, CP, and PDAC. Further validation is warranted in prospective cohorts as developed by the CPDPC.

  View details for DOI 10.1016/j.pan.2019.11.008

  View details for PubMedID 31791885

• Precision Medicine in Pancreatic Disease-Knowledge Gaps and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas Lowe, M. E., Andersen, D. K., Caprioli, R. M., Choudhary, J., Cruz-Monserrate, Z., Dasyam, A. K., Forsmark, C. E., Gorelick, F. S., Gray, J. W., Haupt, M., Kelly, K. A., Olive, K. P., Plevritis, S. K., Rappaport, N., Roth, H. R., Steen, H., Swamidass, S. J., Tirkes, T., Uc, A., Veselkov, K., Whitcomb, D. C., Habtezion, A. 2019; 48 (10): 1250–58

  Abstract

  A workshop on research gaps and opportunities for Precision Medicine in Pancreatic Disease was sponsored by the National Institute of Diabetes and Digestive Kidney Diseases on July 24, 2019, in Pittsburgh. The workshop included an overview lecture on precision medicine in cancer and 4 sessions: (1) general considerations for the application of bioinformatics and artificial intelligence; (2) omics, the combination of risk factors and biomarkers; (3) precision imaging; and (4) gaps, barriers, and needs to move from precision to personalized medicine for pancreatic disease. Current precision medicine approaches and tools were reviewed, and participants identified knowledge gaps and research needs that hinder bringing precision medicine to pancreatic diseases. Most critical were (a) multicenter efforts to collect large-scale patient data sets from multiple data streams in the context of environmental and social factors; (b) new information systems that can collect, annotate, and quantify data to inform disease mechanisms; (c) novel prospective clinical trial designs to test and improve therapies; and (d) a framework for measuring and assessing the value of proposed approaches to the health care system. With these advances, precision medicine can identify patients early in the course of their pancreatic disease and prevent progression to chronic or fatal illness.

  View details for DOI 10.1097/MPA.0000000000001412

  View details for PubMedID 31688587

• Innate and Adaptive Immune Responses Activated by Pancreas Specific Ablation of Atg5 Lee, B., Mareninova, O. A., Dillon, D. L., Gukovskaya, A. S., Gukovsky, I., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2019: 1471

  View details for Web of Science ID 000505712800305

• Local and Systemic Immune Signature Differences During Acute, Recurrent Acute, and Chronic Pancreatitis Progression Using Mass Cytometry Manohar, M., Rubin, S. J., Jones, E. K., Pandol, S. J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2019: 1485

  View details for Web of Science ID 000505712800362

• Immune Profiling of the Human Pancreas in Hereditary and Idiopathic Chronic Pancreatitis Lee, B., Adamska, J. Z., Namkoong, H., Bellin, M. D., Wilhelm, J., Szot, G., Louis, D. M., Davis, M. M., Pandol, S. J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2019: 1471

  View details for Web of Science ID 000505712800304

• STING signalling protects against chronic pancreatitis by modulating Th17 response GUT Zhao, Q., Manohar, M., Wei, Y., Pandol, S. J., Habtezion, A. 2019; 68 (10): 1827-+

  View details for DOI 10.1136/gutjnl-2018-317098

  View details for Web of Science ID 000496491100013

• Transcutaneous vagal nerve stimulation improves symptoms, pain, and gastric emptying in patients with idiopathic gastroparesis Gottfried, A., Adler, E. P., Fernandez-Becker, N., Clarke, J. O., Habtezion, A., Nguyen, L. B. WILEY. 2019

  View details for Web of Science ID 000481874100039

• Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut Niu, N., Lu, P., Yang, Y., He, R., Zhang, L., Shi, J., Wu, J., Yang, M., Zhang, Z., Wang, L., Gao, W., Habtezion, A., Xiao, G. G., Sun, Y., Li, L., Xue, J. 2019

  Abstract

  OBJECTIVE: SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown.DESIGN: TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (Pdx cre Setd2 flox/flox) together with Kras G12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism.RESULTS: SETD2 mutant/lowexpression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis.CONCLUSION: Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.

  View details for DOI 10.1136/gutjnl-2019-318362

  View details for PubMedID 31300513

• Mass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases. Nature communications Rubin, S. J., Bai, L., Haileselassie, Y., Garay, G., Yun, C., Becker, L., Streett, S. E., Sinha, S. R., Habtezion, A. 2019; 10 (1): 2686

  Abstract

  Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients' disease phenotype. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs. Diagnosis and monitoring of disease requires invasive procedures, such as endoscopy and tissue biopsy. Here we report signatures of heterogeneity between disease diagnoses and phenotypes. Using mass cytometry, we analyze leukocyte subsets, characterize their function(s), and examine gut-homing molecule expression in blood and intestinal tissue from healthy and/or IBD subjects. Some signatures persist in IBD despite remission, and many signatures are highly represented by leukocytes that express gut trafficking molecules. Moreover, distinct systemic and local immune signatures suggest patterns of cell localization in disease. Our findings highlight the importance of gut tropic leukocytes in circulation and reveal that blood-based immune signatures differentiate clinically relevant subsets of IBD.

  View details for DOI 10.1038/s41467-019-10387-7

  View details for PubMedID 31217423

• Saffron: The Golden Spice with Therapeutic Properties on Digestive Diseases NUTRIENTS Ashktorab, H., Soleimani, A., Singh, G., Amin, A., Tabtabaei, S., Latella, G., Stein, U., Akhondzadeh, S., Solanki, N., Gondre-Lewis, M. C., Habtezion, A., Brim, H. 2019; 11 (5)

  View details for DOI 10.3390/nu11050943

  View details for Web of Science ID 000471021600003

• Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions GASTROENTEROLOGY Habtezion, A., Gukovskaya, A. S., Pandol, S. J. 2019; 156 (7): 1941–50

  View details for DOI 10.1053/j.gastro.2018.11.082

  View details for Web of Science ID 000465258000002

• Expanded CD14(hi) CD16(-) Immunosuppressive Monocytes Predict Disease Severity in Patients with Acute Pancreatitis JOURNAL OF IMMUNOLOGY Zhang, R., Shi, J., Zhang, R., Ni, J., Habtezion, A., Wang, X., Hu, G., Xue, J. 2019; 202 (9): 2578–84

  View details for DOI 10.4049/jimmunol.1801194

  View details for Web of Science ID 000465364300008

• Recent Insights Into the Pathogenic Mechanism of Pancreatitis Role of Acinar Cell Organelle Disorders PANCREAS Gukovskaya, A. S., Gorelick, F. S., Groblewski, G. E., Mareninova, O. A., Lugea, A., Antonucci, L., Waldron, R. T., Habtezion, A., Karin, M., Pandol, S. J., Gukovsky, I. 2019; 48 (4): 459–70

  View details for DOI 10.1097/MPA.0000000000001298

  View details for Web of Science ID 000466768700010

• Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders. Pancreas Gukovskaya, A. S., Gorelick, F. S., Groblewski, G. E., Mareninova, O. A., Lugea, A., Antonucci, L., Waldron, R. T., Habtezion, A., Karin, M., Pandol, S. J., Gukovsky, I. 2019; 48 (4): 459–70

  Abstract

  Acute pancreatitis (AP) is a potentially lethal inflammatory disease that lacks specific therapy. Damaged pancreatic acinar cells are believed to be the site of AP initiation. The primary function of these cells is the synthesis, storage, and export of digestive enzymes. Beginning in the endoplasmic reticulum and ending with secretion of proteins stored in zymogen granules, distinct pancreatic organelles use ATP produced by mitochondria to move and modify nascent proteins through sequential vesicular compartments. Compartment-specific accessory proteins concentrate cargo and promote vesicular budding, targeting, and fusion. The autophagy-lysosomal-endosomal pathways maintain acinar cell homeostasis by removing damaged/dysfunctional organelles and recycling cell constituents for substrate and energy. Here, we discuss studies in experimental and genetic AP models, primarily from our groups, which show that acinar cell injury is mediated by distinct mechanisms of organelle dysfunction involved in protein synthesis and trafficking, secretion, energy generation, and autophagy. These early AP events (often first manifest by abnormal cytosolic Ca signaling) in the acinar cell trigger the inflammatory and cell death responses of pancreatitis. Manifestations of acinar cell organelle disorders are also prominent in human pancreatitis. Our findings suggest that targeting specific mediators of organelle dysfunction could reduce disease severity.

  View details for PubMedID 30973461

• Expanded CD14hiCD16- Immunosuppressive Monocytes Predict the Severity of Patients with Acute Pancreatitis. Journal of immunology (Baltimore, Md. : 1950) Zhang, R., Shi, J., Zhang, R., Ni, J., Habtezion, A., Wang, X., Hu, G., Xue, J. 2019

  Abstract

  Mild acute pancreatitis (AP) is a self-limiting disease, whereas severe AP has high mortality because of enhanced systemic inflammation and multiple organ failure. In experimental models of AP, infiltration of monocytes and activation of monocyte-derived macrophages largely determine the severity of the disease. Our previous studies have shown that CD11b+Ly-6Chi inflammatory monocytes were mobilized from bone marrow into peripheral blood and inflamed pancreas during the early stage of AP. However, the phenotype and characteristics of circulating monocytes in patients with AP are not well defined. Fifty patients with AP and nine age- and sex-matched healthy volunteers were enrolled in this study. Compared with those of healthy volunteers, the proportion of CD14hiCD16- monocytes and the level of myeloid-related cytokines/chemokines were increased in AP patients within 48 h after disease onset, especially in patients with a severe disease course. Moreover, the increased monocyte proportions were associated with decreased HLA-DR expression and a reduced T cell count. Notably, dynamic changes in circulating CD14hiCD16- monocytes and their HLA-DR expression, as well as in CD4+ T cells, were obviously different between moderate severe AP and severe AP. Last, area under the receiver operating characteristic analysis showed that the combination of CD14hiCD16- monocyte proportions with their HLA-DR level had higher accuracy for predicting the severity of AP. Taken together, the ratio of CD14hiCD16- monocytes and their HLA-DR level might assist in predicting the severity of disease in AP patients at admission and in monitoring patients' clinical status during recovery.

  View details for PubMedID 30894427

• STING signalling protects against chronic pancreatitis by modulating Th17 response. Gut Zhao, Q., Manohar, M., Wei, Y., Pandol, S. J., Habtezion, A. 2019

  Abstract

  OBJECTIVE: Chronic pancreatitis (CP) is an inflammatory disease with progressive fibrosis leading to exocrine and endocrine dysfunction. Currently, there are no approved effective therapies for CP. Stimulator of interferon genes (STING) signalling is a key innate immune sensor of DNA. In this study, we evaluated the role of STING signalling in CP.DESIGN: We used an experimental model of CP to test the effect of STING signalling in STING wild-type and knockout mice as well as bone marrow chimaeras (BMCs). STING was activated using a pharmacological agent. Since we found changes in Th17 cells, we used neutralising and control antibodies to determine the role of IL-17A. The effect of STING signalling was further explored in IL-17A generation and we examined the effect of IL-17A on pancreatic stellate cells (PSCs). Human pancreas from patients with CP and without CP were also stained for IL-17A.RESULTS: STING activation decreased CP-associated pancreatic inflammation and fibrosis, whereas absence of STING led to worsening of the disease. BMCs showed that leucocytes play an important role in STING signalling-mediated amelioration of experimental CP. STING deletion was associated with increased Th17 cell infiltration in the pancreas, whereas STING agonist limited this Th17 response. Importantly, anti-IL-17A antibody treatment mitigated the severity of CP in the absence of STING signalling. STING deficiency promoted Th17 polarisation and PSCs express functional IL-17 receptor by upregulating fibrosis genes. Compared with tumour margins, pancreas from patients with CP had significant increase in IL-17A+ cells.CONCLUSION: Unlike acute pancreatitis, STING activation is protective in CP. STING signalling is important in regulating adaptive immune responses by diminishing generation of IL-17A during CP and presents a novel therapeutic target for CP.

  View details for PubMedID 30705050

• Acute pancreatitis: a multi-faceted set of organellar andcellular interactions. Gastroenterology Habtezion, A., Gukovskaya, A. S., Pandol, S. J. 2019

  View details for PubMedID 30660726

• Age-Related Changes inGut Microbiota AlterPhenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility. Cellular and molecular gastroenterology and hepatology Becker, L., Spear, E. T., Sinha, S. R., Haileselassie, Y., Habtezion, A. 2019; 7 (1): 243

  View details for PubMedID 30585161

• Saffron: The Golden Spice with Therapeutic Properties on Digestive Diseases. Nutrients Ashktorab, H. n., Soleimani, A. n., Singh, G. n., Amr, A. n., Tabtabaei, S. n., Latella, G. n., Stein, U. n., Akhondzadeh, S. n., Solanki, N. n., Gondré-Lewis, M. C., Habtezion, A. n., Brim, H. n. 2019; 11 (5)

  Abstract

  Saffron is a natural compound that has been used for centuries in many parts of the world as a food colorant and additive. It was shown to have the ability to mitigate various disorders through its known anti-inflammatory and anti-oxidant properties. Several studies have shown the effectiveness of saffron in the treatment of various chronic diseases like inflammatory bowel diseases, Alzheimer's, rheumatoid arthritis as well as common malignancies of the colon, stomach, lung, breast, and skin. Modern day drugs generally have unwanted side effects, which led to the current trend to use naturally occurring products with therapeutic properties. In the present review, the objective is to systematically analyze the wealth of information regarding the potential mechanisms of action and the medical use of saffron, the "golden spice", especially in digestive diseases. We summarized saffron influence on microbiome, molecular pathways, and inflammation in gastric, colon, liver cancers, and associated inflammations.

  View details for PubMedID 31027364

• An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice GASTROENTEROLOGY Edderkaoui, M., Chheda, C., Soufi, B., Zayou, F., Hu, R. W., Ramanujan, V., Pan, X., Boros, L. G., Tajbakhsh, J., Madhav, A., Bhowmick, N. A., Wang, Q., Lewis, M., Tuli, R., Habtezion, A., Murali, R., Pandol, S. J. 2018; 155 (6): 1985-+

  Abstract

  Growth, progression, and drug resistance of pancreatic ductal adenocarcinomas (PDACs) have been associated with increased levels and activity of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs). We designed and synthesized molecules that simultaneously inhibit the activities of both enzymes. We tested the effects of one of these molecules, Metavert, in pancreatic cancer cells and mice with pancreatic tumors.We tested the ability of Metavert to bind GSK3B and HDACs using surface plasmon resonance. MIA PaCa-2, Bx-PC3, HPAF-II, and HPDE6 cell lines were incubated with different concentrations of Metavert, with or without paclitaxel or gemcitabine, or with other inhibitors of GSK3B and HDACs; cells were analyzed for apoptosis and migration and by immunoblotting, immunofluorescence, and real-time polymerase chain reaction. Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) mice (2 months old) were given injections of Metavert (5 mg/kg, 3 times/week) or vehicle (control). B6.129J mice with tumors grown from UN-KPC961-Luc cells were given injections of Metavert or vehicle. Tumors and metastases were counted and pancreata were analyzed by immunohistochemistry. Glucose metabolism was measured using 13C-glucose tracer and mass spectroscopy and flow cytometry. Cytokine levels in blood samples were measured using multiplexing enzyme-linked immunosorbent assay.Metavert significantly reduced survival of PDAC cells but not nontransformed cells; the agent reduced markers of the epithelial-to-mesenchymal transition and stem cells in PDAC cell lines. Cells incubated with Metavert in combination with irradiation and paclitaxel or gemcitabine had reduced survival compared with cells incubated with either agent alone; Metavert increased killing of drug-resistant PDAC cells by paclitaxel and gemcitabine. PDAC cells incubated with Metavert acquired normalized glucose metabolism. Administration of Metavert (alone or in combination with gemcitibine) to KPC mice or mice with syngeneic tumors significantly increased their survival times, slowed tumor growth, prevented tumor metastasis, decreased tumor infiltration by tumor-associated macrophages, and decreased blood levels of cytokines.In studies of PDAC cells and 2 mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACs (Metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.

  View details for PubMedID 30144430

• Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Chronic Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas Forsmark, C. E., Andersen, D. K., Farrar, J. T., Golden, M., Habtezion, A., Husain, S. Z., Li, L., Mayerle, J., Pandol, S. J., Uc, A., Zhu, Z., Yadav, D. 2018; 47 (10): 1200–1207

  Abstract

  The lack of effective therapeutic agents specifically tailored for chronic pancreatitis (CP) has hampered clinical care and negatively impacted patients' lives. New mechanistic insights now point to novel therapies, which involve both recently developed and/or repurposed agents. This working group focused on 2 main outcomes for CP: pain and progression of disease. The goal is to frame the essential aspects of trial design including patient-centered outcomes, proposed methods to measure the outcomes of pain and progression, and study design considerations for future trials to facilitate rapid drug development for patients with CP.

  View details for PubMedID 30325858

• PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer PANCREAS Yadav, D., Park, W. G., Fogel, E. L., Li, L., Chari, S. T., Feng, Z., Fisher, W. E., Forsmark, C. E., Jeon, C. Y., Habtezion, A., Hart, P. A., Hughes, S. J., Othman, M. O., Rinaudo, J. S., Pandol, S. J., Tirkes, T., Serrano, J., Srivastava, S., Van Den Eeden, S. K., Whitcomb, D. C., Topazian, M., Conwell, D. L., Consortium Study Chronic 2018; 47 (10): 1229–38

  View details for DOI 10.1097/MPA.0000000000001170

  View details for Web of Science ID 000449304600011

• Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer PANCREAS Hart, P. A., Andersen, D. K., Mather, K. J., Castonguay, A. C., Bajaj, M., Bellin, M. D., Bradley, D., Contreras, N., Habtezion, A., Korc, M., Kudva, Y., Petrov, M. S., Whitcomb, D. C., Yadav, D., Yuan, Y., Rinaudo, J. S., Srivastava, S., Serrano, J., Goodarzi, M. O., Consortium Study Chronic 2018; 47 (10): 1239–43

  View details for DOI 10.1097/MPA.0000000000001168

  View details for Web of Science ID 000449304600012

• Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas Hart, P. A., Andersen, D. K., Mather, K. J., Castonguay, A. C., Bajaj, M., Bellin, M. D., Bradley, D., Contreras, N., Habtezion, A., Korc, M., Kudva, Y., Petrov, M. S., Whitcomb, D. C., Yadav, D., Yuan, Y., Rinaudo, J. A., Srivastava, S., Serrano, J., Goodarzi, M. O., Consortium for the Study of Chronic Pancreatitis, D. 2018; 47 (10): 1239–43

  Abstract

  Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, "Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study," that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.

  View details for PubMedID 30325863

• PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas Yadav, D., Park, W. G., Fogel, E. L., Li, L., Chari, S. T., Feng, Z., Fisher, W. E., Forsmark, C. E., Jeon, C. Y., Habtezion, A., Hart, P. A., Hughes, S. J., Othman, M. O., Rinaudo, J. A., Pandol, S. J., Tirkes, T., Serrano, J., Srivastava, S., Van Den Eeden, S. K., Whitcomb, D. C., Topazian, M., Conwell, D. L. 2018; 47 (10): 1229-1238

  Abstract

  Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.

  View details for DOI 10.1097/MPA.0000000000001170

  View details for PubMedID 30325862

• Interleukin 4 is inactivated via selective disulfide-bond reduction by extracellular thioredoxin. Proceedings of the National Academy of Sciences of the United States of America Plugis, N. M., Weng, N., Zhao, Q., Palanski, B. A., Maecker, H. T., Habtezion, A., Khosla, C. 2018

  Abstract

  Thioredoxin 1 (TRX), an essential intracellular redox regulator, is also secreted by mammalian cells. Recently, we showed that TRX activates extracellular transglutaminase 2 via reduction of an allosteric disulfide bond. In an effort to identify other extracellular substrates of TRX, macrophages derived from THP-1 cells were treated with NP161, a small-molecule inhibitor of secreted TRX. NP161 enhanced cytokine outputs of alternatively activated macrophages, suggesting that extracellular TRX regulated the activity of interleukin 4 (IL-4) and/or interleukin 13 (IL-13). To test this hypothesis, the C35S mutant of human TRX was shown to form a mixed disulfide bond with recombinant IL-4 but not IL-13. Kinetic analysis revealed a kcat/KM value of 8.1 muM-1min-1 for TRX-mediated recognition of IL-4, which established this cytokine as the most selective partner of extracellular TRX to date. Mass spectrometry identified the C46-C99 bond of IL-4 as the target of TRX, consistent with the essential role of this disulfide bond in IL-4 activity. To demonstrate the physiological relevance of our biochemical findings, recombinant TRX was shown to attenuate IL-4-dependent proliferation of cultured TF-1 erythroleukemia cells and also to inhibit the progression of chronic pancreatitis in an IL-4-driven mouse model of this disease. By establishing that IL-4 is posttranslationally regulated by TRX-promoted reduction of a disulfide bond, our findings highlight a novel regulatory mechanism of the type 2 immune response that is specific to IL-4 over IL-13.

  View details for PubMedID 30104382

• Age-related changes in fecal bile acids contributes to altered phenotype of muscularis macrophages and disruption of gastrointestinal motility Becker, L., Spear, E., Habtezion, A. WILEY. 2018

  View details for Web of Science ID 000440928700423

• Deletion of scavenger receptor protects against gastrointestinal dysmotility and muscularis inflammation Spear, E., Becker, L., Habtezion, A. WILEY. 2018

  View details for Web of Science ID 000440928700106

• IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer CANCER RESEARCH He, W., Wu, J., Shi, J., Huo, Y., Dai, W., Geng, J., Lu, P., Yang, M., Fang, Y., Wang, W., Zhang, Z., Habtezion, A., Sun, Y., Xue, J. 2018; 78 (12): 3293–3305

  Abstract

  Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR.

  View details for PubMedID 29572224

• STING Signaling Promotes Inflammation in Experimental AcutePancreatitis. Gastroenterology Zhao, Q., Wei, Y., Pandol, S. J., Li, L., Habtezion, A. 2018; 154 (6): 1822

  Abstract

  BACKGROUND & AIMS: Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP.METHODS: We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI).RESULTS: STING signaling was activated in pancreata from micewith AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI.CONCLUSIONS: In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.

  View details for PubMedID 29425920

• The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop PANCREAS Abbruzzese, J. L., Andersen, D. K., Borrebaeck, C. K., Chari, S. T., Costello, E., Cruz-Monserrate, Z., Eibl, G., Engleman, E. G., Fisher, W. E., Habtezion, A., Kim, S. K., Korc, M., Logsdon, C., Lyssiotis, C. A., Pandol, S. J., Rustgi, A., Wolfe, B. M., Zheng, L., Powers, A. C. 2018; 47 (5): 516–25

  Abstract

  A workshop on "The Interface of Pancreatic Cancer with Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities" was held by the National Institute of Diabetes and Digestive and Kidney Diseases on October 12, 2017. The purpose of the workshop was to explore the relationship and possible mechanisms of the increased risk of pancreatic ductal adenocarcinoma (PDAC) related to diabetes, the role of altered intracellular energy metabolism in PDAC, the mechanisms and biomarkers of diabetes caused by PDAC, the mechanisms of the increased risk of PDAC associated with obesity, and the role of inflammatory events and mediators as contributing causes of the development of PDAC. Workshop faculty reviewed the state of the current knowledge in these areas and made recommendations for future research efforts. Further knowledge is needed to elucidate the basic mechanisms contributing to the role of hyperinsulinemia, hyperglycemia, adipokines, and acute and chronic inflammatory events on the development of PDAC.

  View details for DOI 10.1097/MPA.0000000000001037

  View details for Web of Science ID 000431180300005

  View details for PubMedID 29702529

• Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS Eibl, G., Cruz-Monserrate, Z., Korc, M., Petrov, M. S., Goodarzi, M. O., Fisher, W. E., Habtezion, A., Lugea, A., Pandol, S. J., Hart, P. A., Andersen, D. K., Consortium Study Chronic Pancreati 2018; 118 (4): 555–67

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

  View details for DOI 10.1016/j.jand.2017.07.005

  View details for Web of Science ID 000428262900004

  View details for PubMedID 28919082

  View details for PubMedCentralID PMC5845842

• A Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circulation research Tamosiuniene, R. n., Manouvakhova, O. n., Mesange, P. n., Saito, T. n., Qian, J. n., Sanyal, M. n., Lin, Y. C., Nguyen, L. P., Luria, A. n., Tu, A. B., Sante, J. M., Rabinovitch, M. n., Fitzgerald, D. J., Graham, B. B., Habtezion, A. n., Voelkel, N. F., Aurelian, L. n., Nicolls, M. R. 2018

  Abstract

  Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg-deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymicrnu/rnurats, lacking Tregs, were treated with the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution (IR) before SU5416 administration. Plasma prostacyclin (PGI2) levels were measured. Lung and right ventricles (RVs) were assessed for the expression of the vasoprotective proteins cyclooxygenase-2 (COX-2), prostacyclin synthase (PTGIS), programmed death ligand-1 (PDL-1), and heme oxygenase-1 (HO-1). Inhibitors of these pathways were administered to athymic rats undergoing Treg IR. Finally, human cardiac microvascular endothelial cells co-cultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and estrogen receptor (ER) expression, and culture supernatants were assayed for PGI2 and IL-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented RV fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1 and PDL-1 expression and reduced RV PDL-1 levels. In both sexes, Treg IR protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and programmed death-1 (PD1)/PDL1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. Conclusions: In two animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

  View details for PubMedID 29545367

• Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis GASTROENTEROLOGY Gukovskaya, A. S., Gukovsky, I., Alguel, H., Habtezion, A. 2017; 153 (5): 1212–26

  Abstract

  Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis.

  View details for PubMedID 28918190

• Setting up a Lab: The Early Years CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY Habtezion, A. 2017; 4 (3): 445–46

  View details for PubMedID 29062880

• A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15 FRONTIERS IN IMMUNOLOGY Ocon, B., Pan, J., Dinh, T., Chen, W., Ballet, R., Bscheider, M., Habtezion, A., Tu, H., Zabel, B. A., Butcher, E. C. 2017; 8: 1111

  Abstract

  Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived sushi containing domain-2 binding factor (CSBF), encoded by C10orf99 in the human and 2610528A11Rik in the mouse, functions as a chemokine ligand for GPR15 (GPR15L). GPR15L binds GPR15 and attracts GPR15-expressing T cells including lymphocytes in colon-draining lymph nodes and Vγ3+ thymic precursors of dermal epithelial T cells. Patterns of GPR15L expression by epithelial cells in adult mice and humans suggest a homeostatic role for the chemokine in lymphocyte localization to the large intestines, as well as a role in homing to the epidermis during wound healing or inflammation. GPR15L is also significantly expressed in squamous mucosa of the oral cavity and esophagus with still poorly defined regulation. Identification of the chemotactic activity of GPR15L adds to its reported antibacterial and tumor cell growth regulatory functions and suggests the potential of targeting GPR15L-GPR15 interactions for modulation of mucosal and cutaneous inflammation.

  View details for PubMedID 28936214

• Immunology of pancreatitis and environmental factors CURRENT OPINION IN GASTROENTEROLOGY Lee, B., Zhao, Q., Habtezion, A. 2017; 33 (5): 383–89

  Abstract

  This report reviews recent aspects of pancreatitis immunology and environmental factors that link to development and progression of disease.Limited human and animal model studies have recently attempted to understand immune mechanisms that lead to the pathogenesis of acute and chronic pancreatitis. Based on these studies innate immune responses emerge as critical elements in disease pathogenesis and severity of inflammation. The immune basis for environmental factors such as smoking, which are highly associated with disease progression highlight novel cross talk mechanisms between immune and nonimmune pancreatic cells such as the pancreatic stellate cells.Better understanding of immune responses and signaling pathways are emerging as important contributors in pancreatitis development and progression. Such mechanisms are likely to offer future targetable therapies that can either halt or reverse disease progression.

  View details for PubMedID 28682796

• Editors' Introduction to the Chronic Pancreatitis and Pancreatic Cysts Special Issue. Digestive diseases and sciences Park, W. G., Habtezion, A. 2017

  View details for DOI 10.1007/s10620-017-4613-z

  View details for PubMedID 28523572

• Trafficking receptor signatures define blood plasmablasts responding to tissue-specific immune challenge. JCI insight Seong, Y., Lazarus, N. H., Sutherland, L., Habtezion, A., Abramson, T., He, X., Greenberg, H. B., Butcher, E. C. 2017; 2 (6)

  Abstract

  Antibody-secreting cells are generated in regional lymphoid tissues and traffic as plasmablasts (PBs) via lymph and blood to target sites for local immunity. We used multiparameter flow cytometry to define PB trafficking programs (TPs, combinations of adhesion molecules and chemoattractant receptors) and their imprinting in patients in response to localized infection or immune insults. TPs enriched after infection or autoimmune inflammation of mucosae correlate with sites of immune response or symptoms, with different TPs imprinted during small intestinal, colon, throat, and upper respiratory immune challenge. PBs induced after intramuscular or intradermal influenza vaccination, including flu-specific antibody-secreting cells, display TPs characterized by the lack of mucosal homing receptors. PBs of healthy donors display diverse mucosa-associated TPs, consistent with homeostatic immune activity. Identification of TP signatures of PBs may facilitate noninvasive monitoring of organ-specific immune responses.

  View details for DOI 10.1172/jci.insight.90233

  View details for PubMedID 28352656

• Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut Becker, L., Nguyen, L., Gill, J., Kulkarni, S., Pasricha, P. J., Habtezion, A. 2017

  Abstract

  The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS.Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR.Ageing causes a shift in macrophage polarisation from anti-inflammatory 'M2' to proinflammatory 'M1' that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS.A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

  View details for DOI 10.1136/gutjnl-2016-312940

  View details for PubMedID 28228489

• Regulatory T Cells And Sexual Dimorphism In Pulmonary Hypertension Tamosiuniene, R., Mesange, P., Manouvakhova, O., Saito, T., Qian, J., Sanyal, M., Lin, Y., Nguyen, L., Luria, A., Tu, A., Sante, J., Rabinovitch, M., Voelkel, N., Fitzgerald, D., Habtezion, A., Aurelian, L., Nicolls, M. R. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372504297

• Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. The lancet. Gastroenterology & hepatology Hart, P. A., Bellin, M. D., Andersen, D. K., Bradley, D., Cruz-Monserrate, Z., Forsmark, C. E., Goodarzi, M. O., Habtezion, A., Korc, M., Kudva, Y. C., Pandol, S. J., Yadav, D., Chari, S. T. 2016; 1 (3): 226-237

  Abstract

  Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

  View details for DOI 10.1016/S2468-1253(16)30106-6

  View details for PubMedID 28404095

• Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., Habtezion, A. 2016

  Abstract

  Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4(+) T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

  View details for DOI 10.1053/j.gastro.2016.09.064

  View details for PubMedID 27769811

• Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., Habtezion, A. 2016

  Abstract

  Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4(+) T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

  View details for DOI 10.1053/j.gastro.2016.09.064

  View details for PubMedID 27769811

• Macrophages and pancreatic ductal adenocarcinoma. Cancer letters Habtezion, A., Edderkaoui, M., Pandol, S. J. 2016; 381 (1): 211-216

  Abstract

  Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.

  View details for DOI 10.1016/j.canlet.2015.11.049

  View details for PubMedID 26708507

• Reactive Oxygen Species Imaging in a Mouse Model of Inflammatory Bowel Disease MOLECULAR IMAGING AND BIOLOGY Bronsart, L., Linh Nguyen, L., Habtezion, A., Contag, C. 2016; 18 (4): 473-478

  Abstract

  Reactive oxygen species (ROS) are important contributors to inflammatory bowel disease (IBD); however, there are insufficient tools for their in vivo evaluation.To determine if a chemiluminescent ROS reporter, coelenterazine, would be a useful tool for the detection of immune cell activation, the macrophage cell line (RAW 264.7) was treated with phorbol myristate acetate (PMA). Additionally, coelenterazine was used to monitor the changes in ROS production over time in a mouse model of IBD.In vitro, coelenterazine enabled the dynamic monitoring of the RAW 264.7 cell oxidative burst. In vivo, there were early, preclinical, changes in the localization and magnitude of coelenterazine chemiluminescent foci.Coelenterazine offers a high-throughput method for assessing immune cell activation in culture and provides a means for the in vivo detection and localization of ROS during IBD disease progression.

  View details for DOI 10.1007/s11307-016-0934-0

  View details for Web of Science ID 000379191800001

  View details for PubMedID 26873653

  View details for PubMedCentralID PMC4927601

• HDAC3 mediates smoking-induced pancreatic cancer ONCOTARGET Edderkaoui, M., Xu, S., Chheda, C., Morvaridi, S., Hu, R. W., Grippo, P. J., Mascarinas, E., Principe, D. R., Knudsen, B., Xue, J., Habtezion, A., Uyeminami, D., Pinkerton, K. E., Pandol, S. J. 2016; 7 (7): 7747-7760

  Abstract

  Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease.

  View details for Web of Science ID 000370325900030

• Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology Habtezion, A., Nguyen, L. P., Hadeiba, H., Butcher, E. C. 2016; 150 (2): 340-354

  Abstract

  Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein-coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin α4β7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.

  View details for DOI 10.1053/j.gastro.2015.10.046

  View details for PubMedID 26551552

• Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice FASEB JOURNAL Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nystrom, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. 2015; 29 (12): 5081-5089

  Abstract

  Human mutations in keratin 8 (K8) and keratin 18 (K18), the intermediate filament proteins of hepatocytes, predispose to several liver diseases. K8-null mice develop chronic liver injury and fragile hepatocytes, dysfunctional mitochondria, and Th2-type colitis. We tested the hypothesis that autoantibody formation accompanies the liver damage that associates with K8/K18 absence. Sera from wild-type control, K8-null, and K18-null mice were analyzed by immunoblotting and immunofluorescence staining of cell and mouse tissue homogenates. Autoantibodies to several antigens were identified in 81% of K8-null male mice 8 mo or older. Similar autoantibodies were detected in aging K18-null male mice that had a related liver phenotype but normal colon compared with K8-null mice, suggesting that the autoantibodies are linked to liver rather than colonic disease. However, these autoantibodies were not observed in nontransgenic mice subjected to 4 chronic injury models. The autoantigens are ubiquitous and partition with mitochondria. Mass spectrometry and purified protein analysis identified, mitochondrial HMG-CoA synthase, aldehyde dehydrogenase, and catalase as the primary autoantigens, and glutamate dehydrogenase and epoxide hydrolase-2 as additional autoantigens. Therefore, absence of the hepatocyte keratins results in production of anti-mitochondrial autoantibodies (AMA) that recognize proteins involved in energy metabolism and oxidative stress, raising the possibility that AMA may be found in patients with keratin mutations that associate with liver and other diseases.

  View details for DOI 10.1096/fj.14-269795

  View details for PubMedID 26399787

• Inflammation in acute and chronic pancreatitis. Current opinion in gastroenterology Habtezion, A. 2015; 31 (5): 395-399

  Abstract

  This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis.Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation.Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.

  View details for DOI 10.1097/MOG.0000000000000195

  View details for PubMedID 26107390

• A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies. Gastroenterology Sinha, S. R., Nguyen, L. P., Inayathullah, M., Malkovskiy, A., Habte, F., Rajadas, J., Habtezion, A. 2015; 149 (1): 52-55 e2

  Abstract

  Systemic therapies for inflammatory bowel disease are associated with increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel upon reaching body temperature. Following rectal administration to mice with dextran sulphate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

  View details for DOI 10.1053/j.gastro.2015.04.002

  View details for PubMedID 25863215

• Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism MOLECULAR BIOLOGY OF THE CELL Helenius, T. O., Misiorek, J. O., Nystrom, J. H., Fortelius, L. E., Habtezion, A., Liao, J., Asghar, M. N., Zhang, H., Azhar, S., Omary, M. B., Toivola, D. M. 2015; 26 (12): 2298-2310

  Abstract

  Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8(-/-)) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator-activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions-starvation or ketogenic diet-increase K8(+/+) HMGCS2, whereas this response is blunted in the K8(-/-) colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8(-/-). In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8(-/-) colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.

  View details for DOI 10.1091/mbc.E14-02-0736

  View details for Web of Science ID 000357037300013

  View details for PubMedID 25904331

• Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis NATURE COMMUNICATIONS Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6

  Abstract

  Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

  View details for DOI 10.1038/ncomms8158

  View details for Web of Science ID 000355534000005

  View details for PubMedID 25981357

• Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cellular and molecular life sciences Chang, M., Xue, J., Sharma, V., Habtezion, A. 2015; 72 (6): 1161-1173

  Abstract

  Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.

  View details for DOI 10.1007/s00018-014-1790-1

  View details for PubMedID 25428780

• Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nature immunology Nguyen, L. P., Pan, J., Dinh, T. T., Hadeiba, H., O'Hara, E., Ebtikar, A., Hertweck, A., Gökmen, M. R., Lord, G. M., Jenner, R. G., Butcher, E. C., Habtezion, A. 2015; 16 (2): 207-213

  Abstract

  Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.

  View details for DOI 10.1038/ni.3079

  View details for PubMedID 25531831

• Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins. Chemistry & biology Segal, E., Prestwood, T. R., van der Linden, W. A., Carmi, Y., Bhattacharya, N., Withana, N., Verdoes, M., Habtezion, A., Engleman, E. G., Bogyo, M. 2015; 22 (1): 148-158

  Abstract

  Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

  View details for DOI 10.1016/j.chembiol.2014.11.008

  View details for PubMedID 25579207

  View details for PubMedCentralID PMC4353655

• Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nature communications Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6: 7158-?

  Abstract

  Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

  View details for DOI 10.1038/ncomms8158

  View details for PubMedID 25981357

• Immunodeficiency Mediate The Gender Dimorphism In Pulmonary Hypertension Tamosiuniene, R., Nguyen, L. P., Saito, T., Luria, A., Sante, J., Sung, Y., Rabinovitch, M., Habtezion, A., Nicolls, M. R. AMER THORACIC SOC. 2015

  View details for Web of Science ID 000377582807198

• Pharmacologic therapy for acute pancreatitis WORLD JOURNAL OF GASTROENTEROLOGY Kambhampati, S., Park, W., Habtezion, A. 2014; 20 (45): 16868-16880

  Abstract

  While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis.

  View details for DOI 10.3748/wjg.v20.i45.16868

  View details for Web of Science ID 000346050700007

  View details for PubMedCentralID PMC4258556

• Pharmacologic therapy for acute pancreatitis. World journal of gastroenterology Kambhampati, S., Park, W., Habtezion, A. 2014; 20 (45): 16868-16880

  Abstract

  While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis.

  View details for DOI 10.3748/wjg.v20.i45.16868

  View details for PubMedID 25493000

• Combination of HDAC1 and GSK-3 beta Inhibition as a Treatment Strategy for Pancreatic Cancer Edderkaoui, M., Chheda, C., Xu, S., Principe, D., Grippo, P., Benhaddou, H., Bourhim, M., Habtezion, A., Dale, Y., Pinkerton, K., Pandol, S. LIPPINCOTT WILLIAMS & WILKINS. 2014: 1355

  View details for Web of Science ID 000344362600099

• Targeting Macrophage IL-4R alpha Signaling: a Novel Immune Therapy for Chronic Pancreatitis Xue, J., Sharma, V., Murali, R., Pandol, S. J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2014: 1424

  View details for Web of Science ID 000344362600389

• Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model Edderkaoui, M., Grippo, P., Benhaddou, H., Ouhaddi, Y., Tsukamoto, H., Swartwood, S., Knudsen, B., Goodridge, H. S., Habtezion, A., Go, V., Pandol, S. J. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-4847

  View details for Web of Science ID 000349910203313

• Immune cells and immune-based therapy in pancreatitis. Immunologic research Xue, J., Sharma, V., Habtezion, A. 2014; 58 (2-3): 378-386

  Abstract

  Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.

  View details for DOI 10.1007/s12026-014-8504-5

  View details for PubMedID 24710635

• Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition JOURNAL OF CLINICAL INVESTIGATION Xue, J., Habtezion, A. 2014; 124 (1): 437-447

  Abstract

  The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.

  View details for DOI 10.1172/JCI71362

  View details for Web of Science ID 000329333500048

  View details for PubMedID 24334457

  View details for PubMedCentralID PMC3871246

• Programmed Death 1 (pd1)-Dependent Regulatory T Cell (treg) Protection In The Development Of Pulmonary Hypertension (ph) Tamosiuniene, R., Lin, Y., Sung, Y., Oderup, C., Nguyen, L., Habtezion, A., Nicolls, M. R. AMER THORACIC SOC. 2014

  View details for Web of Science ID 000209838203500

• Alternative Activated Macrophages Activate Pancreatic Stellate Cells and Promote Chronic Pancreatitis Xue, J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2013: 1389

  View details for Web of Science ID 000330468400239

• Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells. Mucosal immunology Zeng, R., Oderup, C., Yuan, R., Lee, M., Habtezion, A., Hadeiba, H., BUTCHER, E. C. 2013; 6 (4): 847-856

  Abstract

  The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that RA also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-μDCs). Pre-μDCs express the gut trafficking receptor α4β7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into CCR9⁺ plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103⁺ intestinal cDCs. Generation of pre-μDCs in vivo in the BM or in vitro is regulated by RA and RA receptor α (RARα) signaling. The frequency of pre-μDCs is reduced in vitamin A-deficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103⁺ cDCs in the gut.

  View details for DOI 10.1038/mi.2012.123

  View details for PubMedID 23235743

  View details for PubMedCentralID PMC3612556

• Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology Zheng, L., Xue, J., Jaffee, E. M., Habtezion, A. 2013; 144 (6): 1230-1240

  Abstract

  Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.

  View details for DOI 10.1053/j.gastro.2012.12.042

  View details for PubMedID 23622132

  View details for PubMedCentralID PMC3641650

• ROLE AND REGULATION OF IL-22 IN THE TREATMENT OF EXPERIMENTAL ACUTE PANCREATITIS 36th Annual Scientific Meeting of the Research-Society-on-Alcoholism Xue, J., Nguyen, D., Habtezion, A. WILEY-BLACKWELL. 2013: 303A–303A

  View details for Web of Science ID 000318998301352

• Inhibiting Heme Oxygenase-1 Abrogates The Protective Effect Of Regulatory T Cells In Pulmonary Hypertension Tamosiuniene, R., Nguyen, L. P., Sung, Y., Lin, Y., Khan, A. M., Sante, J., Habtezion, A., Nicolls, M. R. AMER THORACIC SOC. 2013

  View details for Web of Science ID 000209838402185

• Aryl Hydrocarbon Receptor Regulates Pancreatic IL-22 Production and Protects Mice From Acute Pancreatitis GASTROENTEROLOGY Xue, J., Nguyen, D. T., Habtezion, A. 2012; 143 (6): 1670-1680

  Abstract

  The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice.We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL-ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhR(d) and AhR(-/-) mice).CD4(+) T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL-22(+) CD4(+) T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL-22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP.AhR activation protects mice from AP by inducing expression of IL-22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target.

  View details for DOI 10.1053/j.gastro.2012.08.051

  View details for Web of Science ID 000311505100044

  View details for PubMedID 23022954

  View details for PubMedCentralID PMC3647696

• Aryl Hydrocarbon Receptor Regulates Pancreatic IL-22 and Protects Against Acute Pancreatitis in Mice Xue, J., Nguyen, D. T., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2012: 1414–14

  View details for Web of Science ID 000310360500321

• Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance IMMUNITY Hadeiba, H., Lahl, K., Edalati, A., Oderup, C., Habtezion, A., Pachynski, R., Nguyen, L., Ghodsi, A., Adler, S., Butcher, E. C. 2012; 36 (3): 438-450

  Abstract

  Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.

  View details for DOI 10.1016/j.immuni.2012.01.017

  View details for Web of Science ID 000302048400015

  View details for PubMedID 22444632

  View details for PubMedCentralID PMC3315699

• Therapeutic Role of Carbon Monoxide in Experimental Acute Pancreatitis Xue, J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2011: 1363–63

  View details for Web of Science ID 000296398000264

• Panhematin provides a therapeutic benefit in experimental pancreatitis GUT Habtezion, A., Kwan, R., Akhtar, E., Wanaski, S. P., Collins, S. D., Wong, R. J., Stevenson, D. K., Butcher, E. C., Omary, M. B. 2011; 60 (5): 671-679

  Abstract

  Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.

  View details for DOI 10.1136/gut.2010.217208

  View details for Web of Science ID 000289076700015

  View details for PubMedID 21159893

  View details for PubMedCentralID PMC3580958

• Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Habtezion, A., Toivola, D. M., Asghar, M. N., Kronmal, G. S., Brooks, J. D., Butcher, E. C., Omary, M. B. 2011; 108 (4): 1445-1450

  Abstract

  Keratin 8 (K8) is a major intermediate filament protein present in enterocytes and serves an antiapoptotic function in hepatocytes. K8-null mice develop colonic hyperplasia and colitis that are reversed after antibiotic treatment. To investigate the pathways that underlie the mechanism of colonocyte hyperplasia and the normalization of the colonic phenotype in response to antibiotics, we performed genome-wide microarray analysis. Functional annotation of genes that are differentially regulated in K8(-/-) and K8(+/+) isolated colon crypts (colonocytes) identified apoptosis as a major altered pathway. Exposure of K8(-/-) colonocytes or colon organ ("organoid") cultures, but not K8(-/-) small intestine organoid cultures, to apoptotic stimuli showed, surprisingly, that they are resistant to apoptosis compared with their wild-type counterparts. This resistance is not related to inflammation per se because T-cell receptor α-null (TCR-α(-/-)) and wild-type colon cultures respond similarly upon induction of apoptosis. Following antibiotic treatment, K8(-/-) colonocytes and organ cultures become less resistant to apoptosis and respond similarly to the wild-type colonocytes. Antibiotics also normalize most differentially up-regulated genes, including survivin and β4-integrin. Treatment of K8(-/-) mice with anti-β4-integrin antibody up-regulated survivin, and induced phosphorylation of focal adhesion kinase with decreased activation of caspases. Therefore, unlike the proapoptotic effect of K8 mutation or absence in hepatocytes, lack of K8 confers resistance to colonocyte apoptosis in a microflora-dependent manner.

  View details for DOI 10.1073/pnas.1010833108

  View details for Web of Science ID 000286594800046

  View details for PubMedID 21220329

  View details for PubMedCentralID PMC3029736

• Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Habtezion, A., Kwan, R., Yang, A. L., Morgan, M. E., Akhtar, E., Wanaski, S. P., Collins, S. D., Butcher, E. C., Kamal, A., Omary, M. B. 2011; 300 (1): G12-G20

  Abstract

  Heme oxygenase-1 (HO-1) induction by hemin or Panhematin protects against experimental pancreatitis. As a preclinical first step toward determining whether HO-1 upregulation is a viable target in acute pancreatitis (AP) patients, we tested the hypothesis that HO-1 expression in peripheral blood mononuclear cell (PBMC) subsets of hospitalized patients with mild AP is upregulated then normalizes upon recovery and that cells from AP patients have the potential to upregulate their HO-1 ex vivo if exposed to Panhematin. PBMCs were isolated on days 1 and 3 of hospitalization from the blood of 18 AP patients, and PMBC HO-1 levels were compared with PMBCs of 15 hospitalized controls (HC) and 7 volunteer healthy controls (VC). On day 1 of hospitalization, AP patients compared with VCs had higher HO-1 expression in monocytes and neutrophils. Notably, AP monocyte HO-1 levels decreased significantly upon recovery. Panhematin induced HO-1 in ex vivo cultured AP PBMCs more readily than in HC or VC PBMCs. Furthermore, PBMCs from acutely ill AP patients on day 1 were more responsive to HO-1 induction compared with day 3 upon recovery. Similarly, mouse splenocytes had enhanced HO-1 inducibility as their pancreatitis progressed from mild to severe. In conclusion, AP leads to reversible PBMC HO-1 upregulation that is associated with clinical improvement and involves primarily monocytes. Leukocytes from AP patients or mice with AP are primed for HO-1 induction by Panhematin, which suggests that Panhematin could offer a therapeutic benefit.

  View details for DOI 10.1152/ajpgi.00231.2010

  View details for Web of Science ID 000285744300002

  View details for PubMedID 20966033

  View details for PubMedCentralID PMC3025514

• Diabetic Gastroparesis: An Emerging Role for Macrophages and Heme Oxygenase-1 GASTROENTEROLOGY Habtezion, A., Wiley, J. W. 2010; 138 (7): 2219-2223

  View details for DOI 10.1053/j.gastro.2010.04.028

  View details for Web of Science ID 000278136900010

  View details for PubMedID 20434508

• Intermediate filaments take the heat as stress proteins TRENDS IN CELL BIOLOGY Toivola, D. M., Strnad, P., Habtezion, A., Omary, M. B. 2010; 20 (2): 79-91

  Abstract

  Intermediate filament (IF) proteins and heat shock proteins (HSPs) are large multimember families that share several features, including protein abundance, significant upregulation in response to a variety of stresses, cytoprotective functions, and the phenocopying of several human diseases after IF protein or HSP mutation. We are now coming to understand that these common elements point to IFs as important cellular stress proteins with some roles akin to those already well-characterized for HSPs. Unique functional roles for IFs include protection from mechanical stress, whereas HSPs are characteristically involved in protein folding and as chaperones. Shared IF and HSP cytoprotective roles include inhibition of apoptosis, organelle homeostasis, and scaffolding. In this report, we review data that corroborate the view that IFs function as highly specialized cytoskeletal stress proteins that promote cellular organization and homeostasis.

  View details for DOI 10.1016/j.tcb.2009.11.004

  View details for Web of Science ID 000275156700004

  View details for PubMedID 20045331

  View details for PubMedCentralID PMC2843093

• Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis JOURNAL OF CELL SCIENCE Tao, G., Looi, K. S., Toivola, D. M., Strnad, P., Zhou, Q., Liao, J., Wei, Y., Habtezion, A., Omary, M. B. 2009; 122 (21): 3851-3855

  Abstract

  Absence or mutation of keratins 8 (K8) or 18 (K18) cause predisposition to liver injury and apoptosis. We assessed the mechanisms of hepatocyte keratin-mediated cytoprotection by comparing the protein expression profiles of livers from wild-type and K8-null mice using two-dimensional differential-in-gel-electrophoresis (2D-DIGE) and mass spectrometry. Prominent among the alterations were those of mitochondrial proteins, which were confirmed using 2D-DIGE of purified mitochondria. Ultrastructural analysis showed that mitochondria of livers that lack or have disrupted keratins are significantly smaller than mitochondria of wild-type livers. Immunofluorescence staining showed irregular distribution of mitochondria in keratin-absent or keratin-mutant livers. K8-null livers have decreased ATP content; and K8-null mitochondria have less cytochrome c, increased release of cytochrome c after exposure to Ca(2+) and oxidative stimulation, and a higher sensitivity to Ca(2+)-induced permeability transition. Therefore, keratins play a direct or indirect role in regulating the shape and function of mitochondria. The effects of keratin mutation on mitochondria are likely to contribute to hepatocyte predisposition to apoptosis and oxidative injury, and to play a pathogenic role in keratin-mutation-related human liver disease.

  View details for DOI 10.1242/jcs.051862

  View details for Web of Science ID 000271475600004

  View details for PubMedID 19825937

  View details for PubMedCentralID PMC2773188

• CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease NATURE IMMUNOLOGY Hadeiba, H., Sato, T., Habtezion, A., Oderup, C., Pan, J., Butcher, E. C. 2008; 9 (11): 1253-1260

  Abstract

  Dendritic cells (DCs) are 'professional' antigen-presenting cells that are key in the regulation of immune responses. Here we characterize a unique subset of tolerogenic DCs that expressed the chemokine receptor CCR9 and migrated to the CCR9 ligand CCL25, a chemokine linked to the homing of T cells and DCs to the gut. CCR9(+) DCs were of the plasmacytoid DC (pDC) lineage, had an immature phenotype and rapidly downregulated CCR9 in response to maturation-inducing pDC-restricted Toll-like receptor ligands. CCR9(+) pDCs were potent inducers of regulatory T cell function and suppressed antigen-specific immune responses both in vitro and in vivo, including inhibiting acute graft-versus-host disease induced by allogeneic CD4(+) donor T cells in irradiated recipients. Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues.

  View details for DOI 10.1038/ni.1658

  View details for Web of Science ID 000260248600012

  View details for PubMedID 18836452

  View details for PubMedCentralID PMC2901237

• Hemeoxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: A potential therapeutic target Habtezion, A., Kwan, R., Yang, A. L., Morgan, M. E., Akhtar, E., Wanaski, S. P., Collins, S. M., Butcher, E., Kamal, A., Omary, B. W B SAUNDERS CO-ELSEVIER INC. 2008: A372–A373

  View details for Web of Science ID 000255101502528

• DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27 NATURE IMMUNOLOGY Sigmundsdottir, H., Pan, J., Debes, G. F., Alt, C., Habtezion, A., Soler, D., Butcher, E. C. 2007; 8 (3): 285-293

  Abstract

  During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)(2)D(3), the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis. In contrast, 1,25(OH)(2)D(3) suppressed the gut-homing receptors alpha4beta7 and CCR9. Vitamin D3, the inactive prohormone naturally generated in the skin by exposure to the sun, was processed by dendritic cells and T cells to the active metabolite, providing a mechanism for the local regulation of T cell 'epidermotropism'. Our findings support a model in which dendritic cells process and 'interpret' locally produced metabolites to 'program' T cell homing and microenvironmental positioning.

  View details for DOI 10.1038/ni1433

  View details for Web of Science ID 000244275100014

  View details for PubMedID 17259988

• Short-term homing assay reveals a critical role for lymphocyte function-associated antigen-1 in the hepatic recruitment of lymphocytes in graft-versus-host disease JOURNAL OF HEPATOLOGY Sato, T., Habtezion, A., Beilhack, A., Schulz, S., Butcher, E., Thorlacius, H. 2006; 44 (6): 1132-1140

  Abstract

  The liver is a major target organ of graft versus host disease (GvHD) with massive infiltration of alloreactive lymphocytes resulting in hepatitis and hepatocyte injury. Although adhesive mechanisms have been implicated in the biology of GvHD hepatitis, the identity of homing receptors involved in the initial recruitment of cells from the blood is not known.We have developed a short-term homing assay in a model of murine GvHD. Splenocytes from donors at an active stage of GvHD were injected intravenously into adoptive recipients also undergoing GvHD. The recruitment of cells to the liver was assessed 6h after cell transfer.Activated donor CD8 and CD4 lymphocytes expressed lymphocyte function antigen-1 (LFA-1), alpha4-integrins, and P-selectin binding ligands, and localized more efficiently than naïve T cells. Immunoneutralization of LFA-1 reduced the recruitment of CD8 and CD4 lymphocytes to the liver by more than 60%. Anti-LFA-1 antibody also markedly reduced infiltration of lymphocytes in periportal areas and protected against hepatocellular damage.We demonstrate a critical role of LFA-1 in the recruitment of activated lymphocytes to the liver and in immune-cell mediated hepatitis. LFA-1 may be an effective therapeutic target for protecting the liver following bone marrow transplantation.

  View details for DOI 10.1016/j.jhep.2005.11.042

  View details for Web of Science ID 000237984400016

  View details for PubMedID 16466827

• CD8(+) recent thymic emigrants home to and efficiently repopulate the small intestine epithelium NATURE IMMUNOLOGY Staton, T. L., Habtezion, A., Winslow, M. M., Sato, T., Love, P. E., Butcher, E. C. 2006; 7 (5): 482-488

  Abstract

  Prevailing knowledge dictates that naive alphabeta T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8(+) recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and alpha(4)beta(7) integrin were required for gut entry of CD8(+) RTEs. After T cell receptor stimulation, intestinal CD8(+) RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8(+) RTEs efficiently populated the gut of lymphotoxin-alpha-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive alphabeta T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.

  View details for DOI 10.1038/ni1319

  View details for Web of Science ID 000237008800013

  View details for PubMedID 16582913

• Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction JOURNAL OF CLINICAL INVESTIGATION Nakamichi, I., Habtezion, A., Zhong, B. H., Contag, C. H., BUTCHER, E. C., Omary, M. B. 2005; 115 (11): 3007-3014

  Abstract

  Hemin upregulates heme oxygenase-1 (HO-1), a stress-induced enzyme implicated in protection from a variety of injuries while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. We show that HO-1 is induced in pancreatitis caused by caerulein and more prominently in severe pancreatitis caused by feeding a choline-deficient diet (CDD). Intraperitoneal hemin administration dramatically increases peritoneal and pancreas macrophages that overexpress HO-1 in association with pancreatic induction of the chemoattractants monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha but not RANTES or macrophage inflammatory protein-2. Hemin administration before CDD feeding protected 8 of 8 mice from lethality while 7 of 16 controls died. Protection is mediated by HO-1-overexpressing macrophages since hemin-primed macrophages home to the pancreas after transfer to naive mice and protect from CDD-induced pancreatitis. Suppression of hemin-primed peritoneal cell HO-1 using HO-1-specific small interfering RNA prior to cell transfer abolishes protection from CDD-induced pancreatitis. Similarly, hemin pretreatment in caerulein-induced pancreatitis reduces serum amylase and lipase, decreases pancreatic trypsin generation, and protects from lung injury. Therefore, hemin-like compounds or hemin-activated macrophages may offer novel therapeutic approaches for preventing acute pancreatitis and its pulmonary complication via upregulation of HO-1.

  View details for DOI 10.1172/JCI24912

  View details for Web of Science ID 000233022100011

  View details for PubMedID 16239966

  View details for PubMedCentralID PMC1257535

• Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments TRENDS IN CELL BIOLOGY Toivola, D. M., Tao, G. Z., Habtezion, A., Liao, J., Omary, M. B. 2005; 15 (11): 608-617

  Abstract

  Intermediate filament proteins (IFs) maintain cell and tissue integrity, based on evidence of their polymerization and mechanical properties, abundance and disease-associated phenotypes. This 'traditional' function is now augmented by organelle-related and protein-targeting roles. Mitochondrial location and function depend on intact IFs, as demonstrated for desmin, keratins and neurofilaments. Golgi positioning is regulated by several IFs, and endosomal/lysosomal protein distribution by vimentin. IFs dramatically affect nuclear function and shape and play a role in subcellular and membrane targeting of proteins. These functions have been noted in tissues but in some cases only in cell culture. The IF-related organelle-specific and protein-targeting roles, which are likely interrelated, provide functions beyond cell scaffolding and integrity and contribute to the cytoprotective and tissue-specific functions of IF proteins.

  View details for Web of Science ID 000233732100008

  View details for PubMedID 16202602

• Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment JOURNAL OF CELL SCIENCE Habtezion, A., Toivola, D. M., BUTCHER, E. C., Omary, M. B. 2005; 118 (9): 1971-1980

  Abstract

  Keratin 8 (K8) is the major intermediate filament protein present in intestinal epithelia. Depending on the mouse genetic background, absence of K8 causes embryonic lethality or colonic hyperplasia and colitis. We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis. Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8-/- mice of varying ages. K8-/- mice had a marked increase in TCR(beta)-positive/CD4-positive T cells infiltrating the colon lamina propria, in association with enhanced Th2 cytokine (IL-4, IL-5 and IL-13) production. K8-/- mice show early signs of inflammation even prior to weaning, that increases with age, and their epithelial cells overexpress MHC class II antigens. The chronic colitis is related to increased CD4-positive infiltrating T cells displaying memory and naive phenotypes, and an altered vascular endothelium with aberrant expression of peripheral node addressin. Analysis of normal gut-specific homing molecules, reveals an increased number of alpha(4)beta(7)-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons. Antibiotic treatment markedly decreased colon inflammation and ion transporter AE1/2 mistargeting, indicating that luminal bacteria play an important role in the observed phenotype. Therefore, K8-null mice develop chronic spontaneous Th2-type colitis due to a primary epithelial rather than immune cell defect, which is amenable to antibiotic therapy. These mice provide a model to investigate epithelial-leukocyte and epithelial-microbial cross-talk.

  View details for DOI 10.1242/jcs.02316

  View details for Web of Science ID 000229458700020

  View details for PubMedID 15840656

• Risk factors for low bone density in Crohn's disease INFLAMMATORY BOWEL DISEASES Habtezion, A., Silverberg, M. S., Parkes, R., Mikolainis, S., Steinhart, A. H. 2002; 8 (2): 87-92

  Abstract

  Osteopenia and osteoporosis are prevalent in patients with Crohn's disease (CD). We conducted a cross-sectional study on consecutive patients with CD to assess the prevalence and factors associated with low bone mass density (BMD). One hundred sixty-eight patients with CD were evaluated. Baseline demographics, medical and surgical history, calcium intake, physical activity, steroid use, Harvey Bradshaw Index, blood and urine tests, and dual-energy X-ray absorptiometry were obtained. Sixty-seven (40%) and seventy-five (45%) patients had osteopenia of the femur and spine, respectively. Ten to 11% of patients had osteoporosis. Of the 40 patients who never used steroids, 19 (48%) had osteopenia of the femur and 12 (30%) of the spine. Significant associations were found between BMD and age, body mass index, and serum magnesium. Lifetime steroid use was a weaker predictor of bone loss. Duration of disease did not correlate with BMD when adjusted for age. At follow-up at a mean of 2 years, BMD declined in the femur but not the spine. However, those with ongoing steroid use had lower spine BMD. A significant number of patients with CD have osteopenia. Age was the most important predictor of bone loss. Significant proportion of steroid naive patients had osteopenia, which implies that mechanisms other than steroid use are also involved in bone loss in CD. Disease activity, systemic inflammation, and hormonal and genetic factors may all be important determinants of bone loss in CD.

  View details for Web of Science ID 000174114900003

  View details for PubMedID 11854605