Alisa Mueller, MD, PhD

All Publications

• Fibroblasts in immune responses, inflammatory diseases and therapeutic implications. Nature reviews. Rheumatology Zou, A. E., Kongthong, S., Mueller, A. A., Brenner, M. B. 2025

  Abstract

  Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.

  View details for DOI 10.1038/s41584-025-01259-0

  View details for PubMedID 40369134

  View details for PubMedCentralID 393721

• Wnt signaling drives stromal inflammation in inflammatory arthritis. bioRxiv : the preprint server for biology Mueller, A. A., Zou, A. E., Marsh, L. J., Kemble, S., Nayar, S., Watts, G. F., Murphy, C. L., Taylor, E., Major, T., Gardner, D., Buckley, C. D., Wei, K., Raychaudhuri, S., Korsunsky, I., Filer, A., Croft, A. P., Brenner, M. B. 2025

  Abstract

  The concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation. Yet, therapeutic agents specifically targeting fibroblasts are not available. Here, we find that Wnt receptors and modulators are predominantly expressed in stromal populations in the synovium. Importantly, non-canonical Wnt activation induces robust inflammatory gene expression including an abundance of cytokines and chemokines in synovial fibroblasts in vitro . Strikingly, the addition of Wnt ligands or inhibition of Wnt secretion exacerbates or reduces arthritis severity, respectively, in vivo in a murine model of inflammatory arthritis. These observations are relevant in human disease, as Wnt activation signatures are enhanced in fibroblasts derived from inflamed RA synovial tissue as well as fibroblasts across other inflammatory diseases. Together, these findings implicate Wnt signaling as a major driver of fibroblast-mediated inflammation and joint pathology. They further suggest that targeting the Wnt pathway is a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments and who often express fibroblast-predominant synovial phenotypes.

  View details for DOI 10.1101/2025.01.06.631510

  View details for PubMedID 39829745

  View details for PubMedCentralID PMC11741264

• A PD-1highCD4+ T Cell Population With a Cytotoxic Phenotype is Associated With Interstitial Lung Disease in Systemic Sclerosis. ACR open rheumatology Elahee, M., Mueller, A. A., Wang, R., Marks, K. E., Sasaki, T., Cao, Y., Fava, A., Dellaripa, P. F., Boin, F., Rao, D. A. 2024; 6 (7): 429-439

  Abstract

  T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well-characterized cohort of patients with SSc.Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t-distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays.The frequencies of PD-1highCXCR5+ Tfh cells and PD-1highCXCR5- Tph cells were similar in patients with SSc and controls. t-distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD-1highCXCR5- cells distinguished by expression of HLA-DR and inducible costimulator (ICOS). Among PD-1highCXCR5- cells, only the HLA-DR+ICOS- cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA-DR+ICOS- PD-1highCXCR5- cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA-DR+ICOS-PD-1highCXCR5- cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc.Among PD-1highCXCR5- T cells, a subset of HLA-DR+ICOS- cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.

  View details for DOI 10.1002/acr2.11671

  View details for PubMedID 38698736

  View details for PubMedCentralID PMC11246828

• High-dimensional immunophenotyping reveals immune cell aberrations in patients with undiagnosed inflammatory and autoimmune diseases. The Journal of clinical investigation Mueller, A. A., Sasaki, T., Keegan, J. W., Nguyen, J. P., Griffith, A., Horisberger, A. M., Licata, T., Fieg, E., Cao, Y., Elahee, M., Marks, K. E., Simmons, D. P., Briere, L. C., Cobban, L. A., Pallais, J. C., High, F. A., Walker, M. A., Linnoila, J. J., Sparks, J. A., Holers, V. M., Costenbader, K. H., Sweetser, D. A., Krier, J. B., Loscalzo, J., Lederer, J. A., Rao, D. A. 2023; 133 (24)

  View details for DOI 10.1172/JCI169619

  View details for PubMedID 37874643

  View details for PubMedCentralID PMC10721141

• Laboratory trends, hyperinflammation, and clinical outcomes for patients with a systemic rheumatic disease admitted to hospital for COVID-19: a retrospective, comparative cohort study. The Lancet. Rheumatology Hsu, T. Y., D'Silva, K. M., Patel, N. J., Wang, J., Mueller, A. A., Fu, X., Prisco, L., Martin, L., Vanni, K. M., Zaccardelli, A., Cook, C., Choi, H. K., Zhang, Y., Gravallese, E. M., Wallace, Z. S., Sparks, J. A. 2021; 3 (9): e638-e647

  Abstract

  COVID-19 can induce a hyperinflammatory state, which might lead to poor clinical outcomes. We aimed to assess whether patients with a systemic rheumatic disease might be at increased risk for hyperinflammation and respiratory failure from COVID-19.We did a retrospective, comparative cohort study of patients aged 18 years or older admitted to hospital with PCR-confirmed COVID-19 at Mass General Brigham (Boston, USA). We identified patients by a search of electronic health records and matched patients with a systemic rheumatic disease 1:5 to comparators. We compared individual laboratory results by case status and extracted laboratory results and COVID-19 outcomes for each participant. We calculated the COVID-19-associated hyperinflammation score (cHIS), a composite of six domains (a score of ≥2 indicating hyperinflammation) and used logistic regression to estimate odds ratios (ORs) for COVID-19 outcomes by hyperinflammation and case status.We identified 57 patients with a systemic rheumatic disease and 232 matched comparators who were admitted to hospital with COVID-19 between Jan 30 and July 7, 2020; 38 (67%) patients with a rheumatic disease were female compared with 158 (68%) matched comparators. Patients with a systemic rheumatic disease had higher peak median neutrophil-to-lymphocyte ratio (9·6 [IQR 6·4-22·2] vs 7·8 [4·5-16·5]; p=0·021), lactate dehydrogenase concentration (421 U/L [297-528] vs 345 U/L [254-479]; p=0·044), creatinine concentration (1·2 mg/dL [0·9-2·0] vs 1·0 mg/dL [0·8-1·4], p=0·014), and blood urea nitrogen concentration (31 mg/dL [15-61] vs 23 mg/dL [13-37]; p=0·033) than comparators, but median C-reactive protein concentration (149·4 mg/L [76·4-275·3] vs 116·3 mg/L [58·8-225·9]; p=0·11) was not significantly different. Patients with a systemic rheumatic disease had higher peak median cHIS than comparators (3 [1-5] vs 2 [1-4]; p=0·013). All patients with a peak cHIS of 2 or more had higher odds of admission to intensive care (OR 3·45 [95% CI 1·98-5·99]), mechanical ventilation (66·20 [8·98-487·80]), and in-hospital mortality (16·37 [4·75-56·38]) than patients with a peak cHIS of less than 2. In adjusted analyses, patients with a rheumatic disease had higher odds of admission to intensive care (2·08 [1·09-3·96]) and mechanical ventilation (2·60 [1·32-5·12]) than comparators, but not in-hospital mortality (1.78 [0·79-4·02]). Among patients who were discharged from hospital, risk of rehospitalisation (1·08 [0·37-3·16]) and mortality within 60 days (1·20 [0·58-2·47]) was similar in patients and comparators.Patients with a systemic rheumatic disease who were admitted to hospital for COVID-19 had increased risk for hyperinflammation, kidney injury, admission to intensive care, and mechanical ventilation compared with matched comparators. However, among patients who survived, post-discharge outcomes were not significantly different. The cHIS identified patients with hyperinflammation, which was strongly associated with poor COVID-19 outcomes in both patients with a rheumatic disease and comparators. Clinicians should be aware that patients with systemic rheumatic diseases and COVID-19 could be susceptible to hyperinflammation and poor hospital outcomes.None.

  View details for DOI 10.1016/S2665-9913(21)00140-5

  View details for PubMedID 34095857

  View details for PubMedCentralID PMC8163294

• Protocol for assessing and predicting acute respiratory decline in hospitalized patients. STAR protocols Crowley, C. P., Merriam, L. T., Mueller, A. A., Tamura, T., DeGrado, J. R., Haider, H., Salciccioli, J. D., Kim, E. Y. 2021; 2 (2): 100545

  Abstract

  This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as "mild, progressive, or severe" instead of "ICU versus non-ICU", (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study. For complete details on the use and execution of this protocol, please refer to Mueller et al. (2020).

  View details for DOI 10.1016/j.xpro.2021.100545

  View details for PubMedID 34027496

  View details for PubMedCentralID PMC8131117

• Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host NEW ENGLAND JOURNAL OF MEDICINE Choi, B., Choudhary, M. C., Regan, J., Sparks, J. A., Padera, R. F., Qiu, X., Solomon, I. H., Kuo, H., Boucau, J., Bowman, K., Das Adhikari, U., Winkler, M. L., Mueller, A. A., Hsu, T., Desjardins, M., Baden, L. R., Chan, B. T., Walker, B. D., Lichterfeld, M., Brigl, M., Kwon, D. S., Kanjilal, S., Richardson, E. T., Jonsson, A., Alter, G., Barczak, A. K., Hanage, W. P., Yu, X. G., Gaiha, G. D., Seaman, M. S., Cernadas, M., Li, J. Z. 2020; 383 (23): 2291-2293

  View details for DOI 10.1056/NEJMc2031364

  View details for Web of Science ID 000596577700021

  View details for PubMedID 33176080

  View details for PubMedCentralID PMC7673303

• Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients CELL REPORTS MEDICINE Mueller, A. A., Tamura, T., Crowley, C. P., DeGrado, J. R., Haider, H., Jezmir, J. L., Keras, G., Penn, E. H., Massaro, A. F., Kim, E. Y. 2020; 1 (8): 100144

  Abstract

  In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization.

  View details for DOI 10.1016/j.xcrm.2020.100144

  View details for Web of Science ID 000642323000012

  View details for PubMedID 33163981

  View details for PubMedCentralID PMC7598305

• Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nature communications Du, H. n., Shih, C. H., Wosczyna, M. N., Mueller, A. A., Cho, J. n., Aggarwal, A. n., Rando, T. A., Feldman, B. J. 2017; 8 (1): 669

  Abstract

  Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling.

  View details for PubMedID 28939843

• Intronic polyadenylation of PDGFR alpha in resident stem cells attenuates muscle fibrosis NATURE Mueller, A. A., van Velthoven, C. T., Fukumoto, K. D., Cheung, T. H., Rando, T. A. 2016; 540 (7632): 276-?

  Abstract

  Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle. However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.

  View details for DOI 10.1038/nature20160

  View details for Web of Science ID 000389548700058

  View details for PubMedID 27894125

  View details for PubMedCentralID PMC5384334

• Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration CELL Heredia, J. E., Mukundan, L., Chen, F. M., Mueller, A. A., Deo, R. C., Locksley, R. M., Rando, T. A., Chawla, A. 2013; 153 (2): 376-388

  Abstract

  In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.

  View details for DOI 10.1016/j.cell.2013.02.053

  View details for Web of Science ID 000317349700016

  View details for PubMedID 23582327

  View details for PubMedCentralID PMC3663598

• All's well that ends well: alternative polyadenylation and its implications for stem cell biology CURRENT OPINION IN CELL BIOLOGY Mueller, A. A., Cheung, T. H., Rando, T. A. 2013; 25 (2): 222-232

  Abstract

  Stem cell quiescence, activation, and differentiation are governed by a complex network of molecular pathways. There has been a growing recognition that posttranscriptional modifications, such as alternative polyadenylation (APA) of transcripts, play an important role in regulating gene expression and function. Recent analyses of stem cell populations have suggested that APA controls stem cell fate and behavior. Here, we review recent developments that have shaped our understanding of the control of stem cell behavior by APA and we highlight promising areas for future investigation.

  View details for DOI 10.1016/j.ceb.2012.12.008

  View details for Web of Science ID 000317886100012

  View details for PubMedID 23357469

  View details for PubMedCentralID PMC3615088