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

作者：Thuong Trinh‐Minh, Chih-Wei Chen, Cuong Tran Manh, Yinan Li, Honglin Zhu, Xiang Zhou, Debomita Chakraborty, Yun Zhang, Simon Rauber, Clara Dees, Neng‐Yu Lin, Delf Kah, Richard Gerum, Christina Bergmann, Alexander Kreuter, Christiane Reuter, Florian Groeber‐Becker, Beate Eckes, Oliver Distler, Ben Fabry, Andreas Ramming, Alexandra Schambony, Georg Schett, Jörg H. W. Distler · 发表于：Journal of Clinical Investigation · 年份：2024 · DOI：10.1172/jci159884 · 被引用次数：57 · 研究领域：Wnt/β-catenin signaling in development and cancer、Connective tissue disorders research、Fibroblast Growth Factor Research

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.