PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis - PubMed (original) (raw)

. 2020 Sep;79(9):1227-1233.

doi: 10.1136/annrheumdis-2020-216963. Epub 2020 Jun 1.

Lichong Shen 1, Honglin Zhu 1 2, Katja Dreissigacker 1, Diana Distler 1, Xiang Zhou 1, Andrea Hermina Györfi 1, Christina Bergmann 1, Xianyi Meng 1, Clara Dees 1, Thuong Trinh-Minh 1, Ingo Ludolph 3, Raymund Horch 3, Andreas Ramming 1, Georg Schett 1, Jörg H W Distler 4

Affiliations

PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis

Yun Zhang et al. Ann Rheum Dis. 2020 Sep.

Abstract

Objectives: Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc).

Methods: Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α.

Results: The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis.

Conclusion: PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.

Keywords: fibroblasts; systemic sclerosis; treatment.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

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Conflict of interest statement

Competing interests: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB. JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB. JHWD is stock owner of 4D Science.

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