Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, United Kingdom.
Department of Bioinfomatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Braunschweig, Germany.
Cell Mol Gastroenterol Hepatol. 2022;13(4):1019-1039. doi: 10.1016/j.jcmgh.2021.12.010. Epub 2021 Dec 22.
BACKGROUND & AIMS: Inflammation is the hallmark of chronic liver disease. Metabolism is a key determinant to regulate the activation of immune cells. Here, we define the role of sirtuin 1 (SIRT1), a main metabolic regulator, in controlling the activation of macrophages during cholestatic liver disease and in response to endotoxin.
We have used mice overexpressing SIRT1, which we treated with intraperitoneal lipopolysaccharides or induced cholestasis by bile duct ligation. Bone marrow-derived macrophages were used for mechanistic in vitro studies. Finally, PEPC-Boy mice were used for adoptive transfer experiments to elucidate the impact of SIRT1-overexpressing macrophages in contributing to cholestatic liver disease.
We found that SIRT1 overexpression promotes increased liver inflammation and liver injury after lipopolysaccharide/GalN and bile duct ligation; this was associated with an increased activation of the inflammasome in macrophages. Mechanistically, SIRT1 overexpression associated with the activation of the mammalian target of rapamycin (mTOR) pathway that led to increased activation of macrophages, which showed metabolic rewiring with increased glycolysis and broken tricarboxylic acid cycle in response to endotoxin in vitro. Activation of the SIRT1/mTOR axis in macrophages associated with the activation of the inflammasome and the attenuation of autophagy. Ultimately, in an in vivo model of cholestatic disease, the transplantation of SIRT1-overexpressing myeloid cells contributed to liver injury and fibrosis.
Our study provides novel mechanistic insights into the regulation of macrophages during cholestatic disease and the response to endotoxin, in which the SIRT1/mTOR crosstalk regulates macrophage activation controlling the inflammasome, autophagy and metabolic rewiring.
炎症是慢性肝病的标志。代谢是调节免疫细胞激活的关键决定因素。在这里，我们定义了去乙酰化酶 1（SIRT1）作为主要代谢调节剂在控制胆汁淤积性肝病期间和对内毒素反应时巨噬细胞激活中的作用。
我们使用过表达 SIRT1 的小鼠，并用腹腔内脂多糖或胆管结扎诱导胆汁淤积进行治疗。使用骨髓来源的巨噬细胞进行体外机制研究。最后，使用 PEPC-Boy 小鼠进行过继转移实验，以阐明 SIRT1 过表达的巨噬细胞在促进胆汁淤积性肝病中的作用。
我们发现 SIRT1 过表达可促进脂多糖/GalN 和胆管结扎后肝脏炎症和肝损伤的增加；这与巨噬细胞中炎症小体的激活增加有关。机制上，SIRT1 过表达与哺乳动物雷帕霉素靶蛋白（mTOR）通路的激活相关，导致巨噬细胞的激活增加，这表现为对外毒素的代谢重编程，伴有糖酵解增加和三羧酸循环中断。巨噬细胞中 SIRT1/mTOR 轴的激活与炎症小体的激活和自噬的减弱相关。最终，在胆汁淤积性疾病的体内模型中，SIRT1 过表达的髓样细胞的移植导致肝损伤和纤维化。
我们的研究为胆汁淤积性疾病期间和对内毒素反应时巨噬细胞的调节提供了新的机制见解，其中 SIRT1/mTOR 串扰调节巨噬细胞激活，控制炎症小体、自噬和代谢重编程。
