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Non-canonical WNT5A controls the activation of latent TGFβ to drive fibroblast activation and tissue fibrosis

ABSTRACT: Transforming growth factor β (TGFβ) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGFβ remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGFβ in fibrotic diseases. WNT5A was identified as predominant non-canonical 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 TGFβ. The activation of latent TGFβ requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional Knockout of WNT5A or its downstream targets prevented activation of latent TGFβ, rebalanced TGFβ signaling and ameliorated experimental fibrosis. We thus uncovered a novel mechanism for the aberrant activation of latent TGFβ in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222916 | GEO | 2024/02/29

REPOSITORIES: GEO

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