Trinh-Minh, ThuongThuongTrinh-MinhChen, Chih-WeiChih-WeiChenManh, Cuong TranCuong TranManhLi, Yi-NanYi-NanLiZhu, HonglinHonglinZhuZhou, XiangXiangZhouChakraborty, DebomitaDebomitaChakrabortyZhang, YunYunZhangRauber, SimonSimonRauberDees, ClaraClaraDeesLin, Neng-YuNeng-YuLinKah, DelfDelfKahGerum, RichardRichardGerumBergmann, ChristinaChristinaBergmannKreuter, AlexanderAlexanderKreuterReuter, ChristianeChristianeReuterGroeber-Becker, Florian KaiFlorian KaiGroeber-BeckerEckes, BeateBeateEckesDistler, OliverOliverDistlerFabry, BenBenFabryRamming, AndreasAndreasRammingSchambony, AlexandraAlexandraSchambonySchett, GeorgGeorgSchettDistler, Jörg H.W.Jörg H.W.Distler2024-06-112024-06-112024-05-15https://publica.fraunhofer.de/handle/publica/46958110.1172/JCI159884Transforming 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.enFibroblastsFibrosisMAP Kinase Signaling SystemWnt ProteinsWnt-5a ProteinDDC::600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheitjournal article