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ResearchIn-Press PreviewInfectious disease Open Access | 10.1172/jci.insight.176319

Inhibiting Triggering Receptor Expressed on Myeloid Cells-1 signaling to ameliorate skin fibrosis

Swarna Bale,1 Priyanka Verma,1 Bharath Yalavarthi,1 Matija Bajželj,1 Syed A.M. Hasan,1 Jenna N. Silverman,1 Katherine Broderick,1 Kris A. Shah,1 Timothy Hamill,1 Dinesh Khanna,1 Alexander B. Sigalov,2 Swati Bhattacharyya,1 and John Varga1

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

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1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Verma, P. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Yalavarthi, B. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Bajželj, M. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Hasan, S. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Silverman, J. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

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1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Shah, K. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Hamill, T. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Khanna, D. in: JCI | PubMed | Google Scholar |

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Sigalov, A. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Bhattacharyya, S. in: JCI | PubMed | Google Scholar

1Michigan Scleroderma Program, Division of Rheumatology, Department of Inter, University of Michigan Medical School, Ann Arbor, United States of America

2SignaBlok, Inc., Shrewsbury, United States of America

Find articles by Varga, J. in: JCI | PubMed | Google Scholar

Published October 17, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.176319.
Copyright © 2024, Bale et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 17, 2024 - Version history
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Abstract

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. Transforming growth factor-beta (TGF-β) is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used novel ligand-independent TREM-1 inhibitors in order to investigate the pathogenic role of TREM-1 in SSc, using preclinical models of fibrosis, and explanted SSc skin fibroblasts. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.

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