Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis.
Journal
The Journal of clinical investigation
Journal Volume
134
Journal Issue
10
Start Page
e159884
ISSN
1558-8238
Date Issued
2024-03-26
Author(s)
Trinh-Minh, Thuong
Chen, Chih-Wei
Tran Manh, Cuong
Li, Yi-Nan
Zhu, Honglin
Zhou, Xiang
Chakraborty, Debomita
Zhang, Yun
Rauber, Simon
Dees, Clara
Kah, Delf
Gerum, Richard
Bergmann, Christina
Kreuter, Alexander
Reuter, Christiane
Groeber-Becker, Florian
Eckes, Beate
Distler, Oliver
Fabry, Ben
Ramming, Andreas
Schambony, Alexandra
Schett, Georg
Distler, Jörg Hw
Abstract
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.
Subjects
Dermatology
Fibrosis
Pulmonology
SDGs
Type
journal article