Fu Chen Yang

All Publications

• The TG2/LRP1 Pathway for T Cell Activation by Post-Translationally Modified Antigens. Immunological reviews Sewa, A. S., Yang, F. C., Khosla, C. 2026; 341 (1): e70155

  Abstract

  Post-translational modifications (PTMs) can generate neo-epitopes, modified peptides that evade immune tolerance and trigger immune responses. This review focuses on the TG2/LRP1 pathway as a new paradigm for coupling the formation of post-translationally modified peptides with their effective presentation as T-cell antigens by dendritic cells. Transglutaminase 2 (TG2) catalyzes the Gln → Glu conversion of specific residues in peptides derived from dietary gluten thereby enhancing their affinity for HLA-DQ2, the principal genetic determinant of celiac disease. However, because such modified peptides are scarce in intestinal mucosa, an effective mechanism for lysosomal uptake by antigen-presenting cells (APCs) is necessary. Protein-protein interaction between certain peptide-bound TG2 complexes and the low-density lipoprotein receptor-related protein 1 (LRP1) results in efficient endocytosis of these antigenic peptides along with their concomitant release in the endo-lysosomal compartment as deamidated products. An analogous PTM-driven mechanism for antigen presentation may also operate in autoimmune conditions associated with peptidylarginine deiminase (PADI) activity, such as rheumatoid arthritis (RA). The exquisite cellular selectivity of the TG2/LRP1 pathway has implications not only for understanding its role in autoimmunity but also for its potential exploitation in vaccine design.

  View details for DOI 10.1111/imr.70155

  View details for PubMedID 42552594

• Linking post-translational modification of gluten to antigen presentation: a novel pathway for antigenic gluten presentation in celiac disease Chun, A., Yang, F. OXFORD UNIV PRESS. 2025

  View details for DOI 10.1093/jimmun/vkaf283.2427

  View details for Web of Science ID 001627332200001

• A dendritic cell population responsible for transglutaminase 2-mediated gluten antigen presentation in celiac disease. JCI insight Yang, F. C., Besser, H. A., Chun, H. R., Albertelli, M., Fernandez-Becker, N. Q., Jabri, B., Khosla, C. 2025

  Abstract

  In celiac disease (CeD), a gluten-dependent autoimmune disorder, transglutaminase 2 (TG2) deamidates selected glutamine residues in gluten peptides, while HLA-DQ2 presents deamidated antigens to inflammatory T cells. The cellular sources of pathogenic TG2 and DQ2 are unclear. Using chemical biology tools, we show that intestinal CD103+ dendritic cells (DCs) couple cell-surface TG2 to the endocytic LRP1 receptor to simultaneously deamidate gluten antigens and concentrate them in lysosomes. In DQ2-transgenic mice, CD103+ DCs loaded with deamidated antigens migrate from intestinal lamina propria and Peyer's patches into mesenteric lymph nodes, where they engage T cells. In turn, gluten antigen presentation upregulates intestinal TG2 activity. The tool (HB-230) used to establish a role of CD103+ DCs in gluten antigen presentation and TG2 activation in mice also revealed that the TG2/LRP1 pathway is active in human CD14+ monocytes. Within this population of circulating monocytes, a DC subset with the gut-homing β7-integrin marker is elevated in CeD patients with active disease compared to non-celiac controls or patients on a gluten-free diet. Our findings not only inform the cellular basis for gluten toxicity in CeD but they also highlight the immunologic role of an enigmatic protein of growing therapeutic relevance in CeD and other immune disorders.

  View details for DOI 10.1172/jci.insight.196102

  View details for PubMedID 40875488

• Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naive diffuse large B-cell lymphoma EXPERIMENTAL HEMATOLOGY & ONCOLOGY Wang, H., Yang, F., Yang, C., Liu, Y., Ko, P., Li, C., Tsai, C., Chung, Y., Chen, N. 2023; 12 (1): 35

  Abstract

  Circulating monocytic myeloid-derived suppressive cells (M-MDSCs) are implicated as a poor prognostic factor and cause CAR T-cell failure in diffuse large B-cell lymphoma (DLBCL). Triggering receptors expressed on myeloid cells 2 (TREM2) are a transmembrane glycoprotein that polarize macrophages to anti-inflammation phenotype but have never been explored on M-MDSCs. This study aims to elucidate the expression and clinical impact of surface TREM2 on circulating M-MDSCs derived from DLBCL adults.This prospective, observational study enrolled 100 adults with newly diagnosed and treatment-naïve DLBCL from May 2019 to October 2021. Human circulating M-MDSCs were obtained from freshly isolated peripheral blood, and each patient's surface-TREM2 level on M-MDSCs was normalized via a healthy control at the same performance of flow-cytometry analysis. Murine MDSCs derived from bone marrow (BM-MDSCs) were adopted to assess the link between Trem2 and cytotoxic T lymphocytes.More circulating M-MDSCs at diagnosis of DLBCL predicted worse progression-free (PFS) and overall survival (OS). Patients with higher IPI scores, bone marrow involvement, or lower absolute counts of CD4+ or CD8+ T cells in PB had significantly higher normalized TREM2 levels on M-MDSCs. Additionally, normalized TREM2 levels on M-MDSCs could be grouped into low (< 2%), medium (2-44%), or high (> 44%) levels, and a high normalized TREM2 level on M-MDSCs was proven as an independent prognostic factor for both PFS and OS via multivariate Cox regression analysis and associated with worst PFS and OS. Interestingly, normalized levels of surface TREM2 on M-MDSCs were negatively associated with absolute counts of PB CD8+ T cells and positively correlated with levels of intracellular arginase 1 (ARG1) within M-MDSCs. Wild-type BM-MDSCs had significantly higher mRNA levels of Arg1 and showed more prominent ability to suppress the proliferation of co-cultured CD8+ T cells than BM-MDSCs from Trem2 knockout mice, and the suppressive ability could be impaired by adding Arg1 inhibitors (CB1158) or supplementing L-arginine.In treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

  View details for DOI 10.1186/s40164-023-00399-x

  View details for Web of Science ID 000963502100001

  View details for PubMedID 37029450

  View details for PubMedCentralID PMC10080769

• LRP-1 links post-translational modifications to efficient presentation of celiac disease-specific Tcell antigens. Cell chemical biology Loppinet, E., Besser, H. A., Sewa, A. S., Yang, F., Jabri, B., Khosla, C. 2022

  Abstract

  Celiac disease (CeD) is an autoimmune disorder in which gluten-derived antigens trigger inflammation. Antigenic peptides must undergo site-specific deamidation to be presentable to CD4+ Tcells in an HLA-DQ2 or -DQ8 restricted manner. While the biochemical basis for this post-translational modification is understood, its localization in the patient's intestine remains unknown. Here, we describe a mechanism by which gluten peptides undergo deamidation and concentration in the lysosomes of antigen-presenting cells, explaining how the concentration of gluten peptides necessary to elicit an inflammatory response in CeD patients is achieved. A ternary complex forms between a gluten peptide, transglutaminase-2 (TG2), and ubiquitous plasma protein alpha2-macroglobulin, and is endocytosed by LRP-1. The covalent TG2-peptide adduct undergoes endolysosomal decoupling, yielding the expected deamidated epitope. Our findings invoke a pathogenic role for dendritic cells and/or macrophages in CeD and implicate TG2 in the lysosomal clearance of unwanted self and foreign extracellular proteins.

  View details for DOI 10.1016/j.chembiol.2022.12.002

  View details for PubMedID 36608691

• An oral absorbent, AST-120, restores vascular growth and blood flow in ischemic muscles in diabetic mice via modulation of macrophage transition JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Huang, H., Kuo, C., Chang, T., Chou, R., Chen, I., Yang, F., Chen, N., Lin, S., Wu, C., Huang, P. 2021; 155: 99-110

  Abstract

  Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.

  View details for DOI 10.1016/j.yjmcc.2021.03.001

  View details for Web of Science ID 000653618900002

  View details for PubMedID 33713645

• Upregulation of RelB in the miR-122 knockout mice contributes to increased levels of proinflammatory chemokines/cytokines in the liver and macrophages IMMUNOLOGY LETTERS Hsu, K., Wei, C., Su, Y., Chou, T., Lin, Y., Yang, F., Tsou, A., Hsu, C., Tseng, P., Chen, N., Jeng, K., Leu, C. 2020; 226: 22-30

  Abstract

  MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and it plays an important role in regulating liver metabolism and tumor formation. Previous studies also reveal an anti-inflammatory function of miR-122; however, relatively little is known about the mechanisms by which miR-122 suppresses inflammation. This study aims to search the effect of miR-122 on proinflammatory chemokines/cytokines production in mice.Quantitative real-time PCR, Western blot analysis, and ELISA were performed to examine gene expression. TargetScan, miRanda, and microT v3.0 were used to search for possible miR-122 target sites in the 3'-untranslated regions (3'-UTR) of candidate genes. Luciferase reporter assay and site-directed mutagenesis were applied to verify miR-122 target sequences. LPS was applied to peritoneal macrophages and mice to evaluate inflammatory response.The expression of proinflammatory chemokines, including Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10, and Relb in the livers of miR-122 knockout (KO) mice was increased. We identified Relb as a direct miR-122 target. Overexpressing RelB in the mouse liver increased the expression of Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10. Peritoneal macrophages from miR-122 KO mice had a higher level of RelB, and they showed a stronger NF-κB activation and more TNF-α and IL-6 secretion after LPS stimulation. Overexpression of RelB in a macrophage cell line augmented LPS-induced TNF-α and IL-6 production. miR-122 KO mice showed a greatly increased mortality rate and generated a stronger and lasting inflammatory response to LPS.Deletion of miR-122 caused an upregulation of proinflammatory chemokines and RelB in the liver. Increased RelB may contribute to increases in these chemokine in the liver. Intriguingly, deletion of miR-122 also enhanced the sensitivity of macrophages and mice to LPS. Our results reveal that reducing RelB expression is a new mechanism by which miR-122 regulates inflammation.

  View details for DOI 10.1016/j.imlet.2020.06.015

  View details for Web of Science ID 000563801600004

  View details for PubMedID 32622933

• TREM-1-dependent M1 macrophage polarization restores intestinal epithelium damaged by DSS-induced colitis by activating IL-22-producing innate lymphoid cells JOURNAL OF BIOMEDICAL SCIENCE Yang, F., Chiu, P., Chen, Y., Mak, T. W., Chen, N. 2019; 26: 46

  Abstract

  Triggering receptor expressed on myeloid cells-1 (TREM-1) is highly expressed on macrophages in inflamed intestines and reportedly promotes inflammatory bowel disease (IBD) by augmenting pro-inflammatory responses. To study the mechanism mediated by TREM-1 on macrophages, we generated an independent TREM-1 deficient mouse.Acute colitis was induced in C57BL/6 and TREM-1-deficient mice by the administration of dextran sodium sulfate (DSS). Colonic lamina propria immune cell composition and cytokines were analyzed. An innate lymphoid cell (ILC) co-culture experiment with macrophages was used to analyze IL-22 levels. Exogenous IL-22 and TREM-1-expressing macrophages were supplied to TREM-1-deficient mice for examining their effects on intestinal barrier integrity.In inflamed colons, TREM-1 loss compromised the activation of ILC3 and their production of IL-22, which is required for intestinal barrier integrity. ILC3-mediated IL-22 production depends on IL-1β secreted by M1-polarized macrophages, and we found that TREM-1 deficiency results in a decreased number of IL-1β producing-M1 macrophages in colons exposed to DSS. Accordingly, DSS-mediated damage was ameliorated by supplying exogenous IL-22 and TREM-1-expressing macrophages to TREM-1-deficient mice.TREM-1 plays a crucial role in regulating IL-22 production by ILC3 through modulating M1-macrophage polarization during DSS-induced acute colitis.

  View details for DOI 10.1186/s12929-019-0539-4

  View details for Web of Science ID 000471272700001

  View details for PubMedID 31189465

  View details for PubMedCentralID PMC6560756

• C5L2 is required for C5a-triggered receptor internalization and ERK signaling CELLULAR SIGNALLING Hsu, W., Yang, F., Lin, C., Hsieh, S., Chen, N. 2014; 26 (7): 1409-1419

  Abstract

  C5L2 is a receptor that binds to C5a and belongs to the family of G protein-coupled receptors, but its role in physiological C5a-mediated responses remains under debate. Here we show that, like the canonical C5a receptor C5aR, C5L2 plays a pro-inflammatory role in a murine model of acute experimental colitis. We demonstrate that C5L2 physically interacts with C5aR and is required for optimal C5a-mediated C5aR internalization and associated ERK activation. Abrogation of C5a-induced receptor internalization by treatment with the dynamin inhibitor dynasore(TM) impaired C5a-induced MEK and ERK signaling. Although the presence of C5aR alone was sufficient to recruit the scaffold protein β-arrestin1 to the cell membrane in response to C5a stimulation, it was inadequate to mediate AP2 recruitment and subsequent C5aR internalization. Expression of C5L2 allowed normal internalization of C5aR in response to C5a stimulation, followed by normal ERK signaling. Thus, our work reveals an essential role for C5L2 in C5a-triggered, AP2-dependent C5aR internalization and downstream ERK signaling.

  View details for DOI 10.1016/j.cellsig.2014.02.021

  View details for Web of Science ID 000336820000006

  View details for PubMedID 24631530

• TREM-1 Promotes Survival during <i>Klebsiella pneumoniae</i> Liver Abscess in Mice INFECTION AND IMMUNITY Lin, Y., Tseng, K., Yeh, Y., Yang, F., Fung, C., Chen, N. 2014; 82 (3): 1335-1342

  Abstract

  Klebsiella pneumoniae liver abscess (KPLA) is prevalent in East Asia. Liver abscess can develop after translocation of K. pneumoniae from a patient's bowel into the liver via the portal circulation. TREM-1 (triggering receptor expressed on myeloid cells 1) amplifies inflammatory signaling during infection, but its role in KPLA is poorly understood. We used an animal study to characterize the role of TREM-1 in KPLA. We compared survival rates, bacterial burdens in tissues, inflammatory cytokine levels, and histology findings between wild-type and Trem-1 knockout (KO) mice after oral inoculation of capsular type K1 K. pneumoniae. Translocation of K. pneumoniae to mesenteric lymph nodes and liver was examined, and intestinal permeability, antimicrobial peptide expression, and the clearance of K. pneumoniae in the small intestine were determined. In the absence of TREM-1, KPLA model mice showed increased K. pneumoniae dissemination, enhanced liver and systemic inflammation, and reduced survival. Impaired bacterial clearance in the small intestine causes enhanced K. pneumoniae translocation, which renders Trem-1 KO mice more susceptible to K. pneumoniae oral infection. In conclusion, TREM-1-mediated bacterial clearance in the small intestine is an important immune response against K. pneumoniae. TREM-1 deficiency enhances K. pneumoniae translocation in the small intestine and increases mortality rates in mice with KPLA.

  View details for DOI 10.1128/IAI.01347-13

  View details for Web of Science ID 000333190900044

  View details for PubMedID 24396044

  View details for PubMedCentralID PMC3957993

• Characterization of Ertapenem-Resistant <i>Enterobacter cloacae</i> in a Taiwanese University Hospital JOURNAL OF CLINICAL MICROBIOLOGY Yang, F., Yan, J., Hung, K., Wu, J. 2012; 50 (2): 223-226

  Abstract

  The emergence of carbapenem resistance in Enterobacteriaceae has become a great concern. The aim of this study was to characterize ertapenem-resistant Enterobacter cloacae isolates from a Taiwanese university hospital. A total of 355 nonduplicated E. cloacae isolates collected in 2007 were analyzed by antimicrobial susceptibility testing with and without an inhibitor of efflux pumps and AmpC β-lactamase. The phenotype of extended-spectrum β-lactamase (ESBL), profile of outer membrane proteins (OMPs), and clonal relatedness were investigated by the double-disk synergy test, urea/SDS-PAGE, and pulsed-field gel electrophoresis (PFGE), respectively. β-Lactamase genes were examined by PCR and sequencing, and the expression of efflux pump gene acrB was evaluated by reverse transcription-PCR. The contribution of porin deficiency to resistance was investigated by restoring functional porin genes on plasmids. We demonstrated that ertapenem resistance was prevalent (53/355; 14.9%) in E. cloacae. Among the strains, IMP-8, SHV-12, and TEM-1 β-lactamases were identified in 3 (5.7%), 40 (75.5%), and 46 (86.8%) isolates, respectively. PFGE showed clonal diversity among these isolates. Phenotypes of ESBL, AmpC β-lactamase overproduction, an active efflux pump, and change in the expression of OMPs were found in 18 (34%), 11 (20.8%), 51 (96.2%), and 23 (43.4%) of ertapenem-resistant strains, respectively. Ertapenem MICs were restored in strains with OmpC and OmpF expression plasmids. This study suggests that ESBL, AmpC β-lactamase overproduction, and decreased OMP expression combined with an active efflux pump contribute to the ertapenem resistance of E. cloacae. The presence of IMP-8 may also play a partial role in ertapenem resistance in Taiwan.

  View details for DOI 10.1128/JCM.01263-11

  View details for Web of Science ID 000299998000003

  View details for PubMedID 22135256

  View details for PubMedCentralID PMC3264168

• Prevalence and characteristics of ertapenem-nonsusceptible Escherichia coli in a Taiwanese university hospital, 1999 to 2007 EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES Yan, J. J., Wu, J. J., Lee, C. C., Ko, W. C., Yang, F. C. 2010; 29 (11): 1417-1425

  Abstract

  The present study was conducted to investigate the prevalence and characteristics of ertapenem-nonsusceptible (ETP-NS) Escherichia coli in a Taiwanese university. A total of 9,722 isolates collected in 1999, 2003, 2005, and 2007 were examined. Overall, 1.0% of all isolates from 66 patients were interpreted as ETP-NS on the basis of the disk diffusion test result. Most of these isolates were clonally unrelated and showed low-level ertapenem resistance, the production of CMY-2 cephalosporinase (86.4%), and decreased expression of the OmpF (97.0%) and/or OmpC (56.1%) porins. No carbapenemase was detected. The decreased porin expression was associated with disruptions of ompF or ompC in only about one-third of the ETP-NS isolates. During the study period, the prevalence of ETP-NS strains increased from 0.1 to 1.7%, accompanying an increase (0.8 to 17.6%) in the prevalence of CMY-2 producers. Coexistent or pre-existing clonally related ertapenem-susceptible (ETP-S) E. coli isolates were identified in 47.0% of all case patients, and almost all of the ETP-S isolates had the same β-lactamases as the ETP-NS isolates. Our study results suggest the restricted use of extended-spectrum cephalosporins to hinder the emergence and prevalence of carbapenem resistance in E. coli, which may arise by the accumulation of multiple resistance determinants.

  View details for DOI 10.1007/s10096-010-1020-1

  View details for Web of Science ID 000283507500014

  View details for PubMedID 20700614