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

• Published in: Annals of the rheumatic diseases Vol. 79; no. 9; pp. 1227 - 1233
• Main Authors: Zhang, Yun, Shen, Lichong, Zhu, Honglin, Dreissigacker, Katja, Distler, Diana, Zhou, Xiang, Györfi, Andrea Hermina, Bergmann, Christina, Meng, Xianyi, Dees, Clara, Trinh-Minh, Thuong, Ludolph, Ingo, Horch, Raymund, Ramming, Andreas, Schett, Georg, Distler, Jörg H W
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.09.2020
• Subjects: Adenoviruses; Animal models; Autophagy; Biopsy; Bleomycin; Collagen; Experiments; Fibroblasts; Fibrosis; Gene expression; Growth factors; Hypoxia; Immunofluorescence; Pathogenesis; Phagocytosis; Polyclonal antibodies; Scleroderma; Smooth muscle; Systemic sclerosis; Transcription; Transcription factors; Transforming growth factor-b; Netherlands; California; United States > US; Massachusetts; Germany
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2020-216963

ObjectivesCoactivators 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).MethodsExpression 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.ResultsThe 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.ConclusionPGC-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.