Jiangsu Key Laboratory of Molecular and Translational Cancer Research, The Affiliated Cancer Hospital (Jiangsu Cancer Hospital), Nanjing Medical University, Nanjing, China.
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.
Front Immunol. 2021 Feb 22;11:609060. doi: 10.3389/fimmu.2020.609060. eCollection 2020.
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.
非酒精性脂肪性肝炎（NASH）是一种与肝脏代谢和炎症失调相关的慢性肝脏疾病。G 蛋白偶联胆汁酸受体 1（TGR5）是一种细胞表面受体，参与多种代谢途径。然而，TGR5 在调节 NASH 中巨噬细胞固有免疫激活的功能尚不清楚。在这里，我们发现 TGR5 在 NASH 患者和小鼠的肝组织中表达降低。与野生型（WT）小鼠相比，TGR5 敲除（TGR5）小鼠表现出更严重的肝损伤、更高水平的促炎因子和增强的 M1 巨噬细胞极化。此外，TGR5 缺乏通过促进 NLRP3 炎性小体激活和半胱天冬酶-1 切割促进 M1 巨噬细胞极化。总之，我们的研究结果表明，TGR5 信号通路减弱了 NASH 中的肝脂肪变性和炎症，并抑制了 NLRP3 介导的 M1 巨噬细胞极化。
