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

Trinh-Minh T, Chen CW, Tran-Manh C, Li YN, Zhu H, Zhou X, Chakraborty D, Zhang Y, Rauber S, Dees C, Lin NY, Kah DTE, Gerum R, Bergmann C, Kreuter A, Reuter C, Groeber-Becker F, Eckes B, Distler O, Fabry B, Ramming A, Schambony A, Schett G, Distler JHW (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 134

Journal Issue: 10

DOI: 10.1172/JCI159884

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 with CRIS profile

Chih-Wei Chen Lehrstuhl für Entwicklungsbiologie (Ebio) Debomita Chakraborty Department of Medicine 3 – Rheumatology and Immunology Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Neng-Yu Lin Lehrstuhl für Tierphysiologie Delf-Thorge Eric Kah Lehrstuhl für Biophysik Richard Gerum Lehrstuhl für Biophysik Christina Bergmann Department of Medicine 3 – Rheumatology and Immunology Ben Fabry Lehrstuhl für Biophysik Andreas Ramming Medizinische Fakultät Alexandra Schambony Naturwissenschaftliche Fakultät Georg Schett Lehrstuhl für Innere Medizin III

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Universität zu Köln DE Germany (DE) Universitätsklinikum Düsseldorf DE Germany (DE) Fraunhofer Institut für Silicatforschung (ISC) DE Germany (DE) HELIOS Kliniken DE Germany (DE)

How to cite

APA:

Trinh-Minh, T., Chen, C.-W., Tran-Manh, C., Li, Y.N., Zhu, H., Zhou, X.,... Distler, J.H.W. (2024). Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis. Journal of Clinical Investigation, 134(10). https://doi.org/10.1172/JCI159884

MLA:

Trinh-Minh, Thuong, et al. "Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis." Journal of Clinical Investigation 134.10 (2024).

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