TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis

Clara Dees, Sebastian Pötter, Yun Zhang, Christina Bergmann, Xiang Zhou, Markus Luber, Thomas Wohlfahrt, Emmanuel Karouzakis, Andreas Ramming, Kolja Gelse, Akihiko Yoshimura, Rudolf Jaenisch, Oliver Distler, Georg Schett, Jörg H.W. Distler

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Abstract

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.

Original languageEnglish
Pages (from-to)2347-2363
Number of pages17
JournalJournal of Clinical Investigation
Volume130
Issue number5
DOIs
Publication statusPublished - 2020 May 1

ASJC Scopus subject areas

  • Medicine(all)

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    Dees, C., Pötter, S., Zhang, Y., Bergmann, C., Zhou, X., Luber, M., Wohlfahrt, T., Karouzakis, E., Ramming, A., Gelse, K., Yoshimura, A., Jaenisch, R., Distler, O., Schett, G., & Distler, J. H. W. (2020). TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. Journal of Clinical Investigation, 130(5), 2347-2363. https://doi.org/10.1172/JCI122462