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

• Published in: The Journal of clinical investigation Vol. 134; no. 10; pp. 1 - 16
• Main Authors: Trinh-Minh, Thuong, Chen, Chih-Wei, Manh, Cuong Tran, Li, Yi-Nan, Zhu, Honglin, Zhou, Xiang, Chakraborty, Debomita, Zhang, Yun, Räuber, Simon, Dees, Clara, Lin, Neng-Yu, 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 H W
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.05.2024
• Subjects: Collagen; Cytoskeleton; Extracellular matrix; Fibroblasts; Fibrosis; Genes; Graft versus host disease; Graft-versus-host reaction; Growth factors; Kinases; Ligands; Lung diseases; Lungs; Pathogenesis; Proteins; Pulmonary fibrosis; Scleroderma; Systemic sclerosis; Transforming growth factor-b; Wnt protein
• ISSN: 0021-9738; 1558-8238
• 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-ß remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-ß 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.