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Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis
Thuong Trinh-Minh, … , Georg Schett, Jörg H.W. Distler
Thuong Trinh-Minh, … , Georg Schett, Jörg H.W. Distler
Published May 15, 2024
Citation Information: J Clin Invest. 2024;134(10):e159884. https://doi.org/10.1172/JCI159884.
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Research Article Dermatology Pulmonology

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

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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.

Authors

Thuong Trinh-Minh, Chih-Wei Chen, Cuong Tran Manh, Yi-Nan 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

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ISSN: 0021-9738 (print), 1558-8238 (online)

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