Inhibiting triggering receptor expressed on myeloid cells 1 signaling to ameliorate skin fibrosis

JCI Insight. 2024 Dec 6;9(23):e176319. doi: 10.1172/jci.insight.176319.

Abstract

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. 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 potentially novel ligand-independent TREM-1 inhibitors in preclinical models of fibrosis and explanted SSc skin fibroblasts in order to investigate the pathogenic role of TREM-1 in SSc. 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.

Keywords: Autoimmune diseases; Autoimmunity; Infectious disease; Rheumatology.

MeSH terms

  • Animals
  • Bleomycin* / toxicity
  • Disease Models, Animal
  • Female
  • Fibroblasts* / metabolism
  • Fibrosis*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Scleroderma, Systemic* / drug therapy
  • Scleroderma, Systemic* / metabolism
  • Scleroderma, Systemic* / pathology
  • Signal Transduction*
  • Skin* / metabolism
  • Skin* / pathology
  • Triggering Receptor Expressed on Myeloid Cells-1* / antagonists & inhibitors
  • Triggering Receptor Expressed on Myeloid Cells-1* / metabolism

Substances

  • Triggering Receptor Expressed on Myeloid Cells-1
  • Bleomycin
  • TREM1 protein, mouse