Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

Sci Adv. 2019 Dec 4;5(12):eaay0370. doi: 10.1126/sciadv.aay0370. eCollection 2019 Dec.

Abstract

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dupuytren Contracture / drug therapy
  • Dupuytren Contracture / genetics*
  • Dupuytren Contracture / immunology
  • Dupuytren Contracture / pathology
  • Fibrosis / drug therapy
  • Fibrosis / genetics*
  • Fibrosis / immunology
  • Fibrosis / pathology
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-33 / genetics*
  • Macrophages / immunology
  • Macrophages / pathology
  • Molecular Targeted Therapy
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Signal Transduction / genetics
  • Single-Cell Analysis / methods
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • IL33 protein, human
  • Interleukin-33
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha