Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis

J Clin Invest. 2024 Mar 26;134(10):e159884. doi: 10.1172/JCI159884.


Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

Keywords: Dermatology; Fibrosis; Pulmonology.

MeSH terms

  • Animals
  • Fibroblasts* / metabolism
  • Fibroblasts* / pathology
  • Fibrosis*
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Signal Transduction
  • Transforming Growth Factor beta* / genetics
  • Transforming Growth Factor beta* / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt-5a Protein* / genetics
  • Wnt-5a Protein* / metabolism
  • rho-Associated Kinases* / genetics
  • rho-Associated Kinases* / metabolism