PGC-1α regulates endoplasmic reticulum stress in IPF-derived fibroblasts

• Published in: International immunopharmacology 2024-09, Vol.138, p.112514, Article 112514
• Main Authors: Xu, Qinghua, Liu, Huarui, Ding, Shiwen Fan, Xiaorui, Lv, Wenting, Jiang, Yuxian, Liang, Yi, Xu, Hongyang, Dai, Jinghong
• Format: Article
• Language: English
• Subjects: Animals; Bleomycin; Cells, Cultured; Disease Models, Animal; Endoplasmic Reticulum Stress; Female; Fibroblasts - metabolism; Humans; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Lung - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phenylbutyrates - pharmacology
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112514

•PGC-1α as a potential target for IPF.•Endoplasmic reticulum stress participates the differentiation of fibroblasts into myofibroblast.•Knocking down of PGC-1α in lung fibroblasts promotes fibrosis of the lung.•Knocking down of PGC-1α in lung fibroblasts promotes endoplasmic reticulum stress of the lung fibroblasts.•Over-expressing of PGC-1α in lung fibroblasts attenuates the fibrosis of bleomycin-induced lung fibrosis of mice through inhibiting endoplasmic reticulum stress. Idiopathic pulmonary fibrosis (IPF) is considered to be associated with aging. Both ER stress and the unfolded protein response (UPR) have been associated with pulmonary fibrosis via key mechanisms including AEC apoptosis, EMT, altered myofibroblast differentiation, and M2 macrophage polarization. A relationship between ER stress and aging has also been demonstrated in vitro, with increased p16 and p21 levels seen in lung epithelial cells of older IPF patients. The mechanism underlying ER stress regulation of IPF fibroblasts is still unclear. In this study, we aimed to delineate ER stress regulation in IPF-derived fibroblasts. Here, we found that ER stress markers (p-eIF2α, p-IREα, ATF6) and fibrosis markers (α-SMA and Collagen-I) were significantly increased in lung tissues of IPF patients and bleomycin-induced mouse models. Notably, the expression of PGC-1α was decreased in fibroblasts. In vivo experiments were designed using an AAV-6 vector mediated conditional PGC-1α knockout driven by a specific α-SMA promoter. Ablation of PGC-1α expression in fibroblasts promoted ER stress and supported the development of pulmonary fibrosis in a bleomycin-induced mouse model. In another experimental group, mice with conditional knockout of PGC-1α in fibroblasts and injected intraperitoneally with 4-PBA (an endoplasmic reticulum stress inhibitor) were protected from lung fibrosis. We further constructed an AAV-6 vector mediated PGC-1α overexpression model driven by a specific Collagen-I promoter. Overexpression of PGC-1α in fibroblasts suppressed ER stress and attenuated development of pulmonary fibrosis in bleomycin-induced mouse models. Taken together, this study identified PGC-1α as a promising target for developing novel therapeutic options for the treatment of lung fibrosis.