PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis
- 1 June 2020
- journal article
- research article
- Published by BMJ in Annals Of The Rheumatic Diseases
- Vol. 79 (9), 1227-1233
- https://doi.org/10.1136/annrheumdis-2020-216963
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
Funding Information
- Medicine of the Ernst Jung Foundation. (a Career Support Award)
- IZKF in Erlangen (grants J40 and A64)
- Deutsche Forschungsgemeinschaft (DI 1537/9-1 and -2, DI 1537/11-1, DI 1537/12-1, DI, SFB CRC1181 (project C01) and SFB TR221/ project n)
- ELAN-Foundation Erlangen (grant 14-12-17-1-Bergmann)
- Else-Kröner-Fresenius-Foundation (2014_A47 and 2014_A184)
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