Non-canonical WNT5A promotes cytoskeletal rearrangement and ITGAV clustering via JNK and ROCK to control the activation of latent TGFβ

Document Type
Doctoral Thesis
Granting Institution
Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Naturwissenschaftliche Fakultät
Issue Date
Trinh, Thuong

Systemic sclerosis (SSc), also known as scleroderma, is a chronic autoimmune disorder distinguished by three key characteristics: vasculopathy, autoimmunity or inflammation, and fibrosis. Chronic fibroblast activation results in an increase in dermal extracellular matrix deposition. Persistent activation of fibroblasts is an unifying factor of fibrotic disorders, although the underlying mechanisms are not well characterized. The prolonged activation of fibroblasts is triggered by aberrant activation of transforming growth factor beta (TGFβ). Even though great progress has been made in characterizing the biochemical mechanisms underpinning the activation of latent TGFβ, the molecular control of these events remains unknown. Dr. Chih-Wei Chen's dissertation indicated that WNT5A might possibly activate latent TGFβ to promote fibroblast activation and tissue fibrosis. In this dissertation, we sought to elucidate the molecular processes underlying the WNT5A-induced activation of latent TGFβ. I intend to elucidate the intracellular signaling cascades triggered by WNT5A, the gene set controlled by WNT5A in fibroblasts, and the molecular processes that transform these signals into the activation of latent TGFβ. In addition, I aim to determine the efficacy of targeted inactivation of identified downstream targets in inhibiting WNT5A-induced activation of latent TGFβ and related fibroblast activation and tissue fibrosis. Our results show that WNT5A/JNK/ROCK signaling plays a critical role in fibrotic disorders by quickly coordinating the activation of latent TGFβ. In fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, WNT5A has been identified as the predominant non-canonical WNT ligand, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activating latent TGFβ. Rapid JNK- and ROCK-dependent cytoskeletal rearrangements, as well as integrin alpha V (ITGAV), are required for the activation of latent TGFβ. Targeting any of the essential components of this system by deletion of WNT5A (as shown in a previous work) or inhibition of JNK, ROCK, ITGAV, or actin-polymerization prevented activation of latent TGFβ, restored TGFβ signaling, and ameliorated experimental fibrosis. Thus, we identified a novel pathway for the abnormal activation of latent TGFβ in fibrotic disorders and presented evidence for targeting WNT5A/JNK/ROCK signaling as a potential therapeutic strategy in fibrotic diseases.

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