Targeting TGR5 Ameliorates Pulmonary Fibrosis by Regulating TGF-β1 Associated Signaling Pathways

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease with high morbidity and mortality. Recently, TGR5 has been identified as a critical regulatory factor involved in inflammation and cancer. However, its function in pulmonary fibrosis remains unclear. Here, we first reported that TGR5 was overexpressed in the hyperplastic alveolar epithelial cells overlying fibroblastic foci in lung tissues of IPF patients, while mesenchymal cells in areas of fibrosis also had scattered TGR5 staining. In vitro study, TGR5 knockdown effectively inhibited TGF-β1-induced alveolar epithelial cells (AECs) activation and fibroblasts proliferation, motility and differentiation. Mechanically, TGR5 promoted EMT process in lung fibrogenesis by the Smad2/3 and Akt/Erk signaling pathways, which could be potently blocked by TGF β receptor I inhibitor LY2157299 or Akt inhibitor MK2206. Furthermore, the TGR5 expression was elevated in animal models of bleomycin (BLM)-induced pulmonary fibrosis. Our data further revealed that the degree of lung fibrosis was significantly alleviated in TGR5 knockout mice, which was accompanied by prominent decreases in TGF-β1 expression, repression of EMT process and releasing of inflammatory and fibrogenic cytokines. Collectively, this study demonstrated that TGR5 exerted a profibrogenic role in pulmonary fibrosis, thus opening up a novel therapeutic opportunity for pulmonary fibrosis. Funding Statement: This study was supported by Grants from the National Natural Science Foundation of China (Grant No. 81874314, 81903633 and 81600044). Declaration of Interests: All authors reviewed the manuscript and all declare no conflict of interest. Ethics Approval Statement: All medical research was approved by the ethics committees of Ren Ji Hospital.