Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Viral Immunol. 2022 Apr;35(3):223-235. doi: 10.1089/vim.2021.0101.
Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis.
脂质积累和炎症共同作用，导致、维持和进一步发展慢性肝病。丙型肝炎病毒 (HCV) 感染诱导肝巨噬细胞发生代谢和免疫变化，促进脂质积累和炎症，协同作用并最终导致脂肪性肝炎和纤维化的发生。慢性 HCV 患者的肝脏巨噬细胞增加，胆固醇代谢紊乱，炎症介质发生改变。虽然 HCV 诱导的炎症介质变化已有相关记载，但 HCV 如何引发巨噬细胞的代谢变化尚不清楚。在本报告中，我们研究了巨噬细胞感知 HCV 引起代谢损伤和随后免疫功能障碍的机制。我们证明了巨噬细胞中 HCV 蛋白和 RNA 的动力学与肝细胞明显不同。在巨噬细胞中，暴露于 HCV 后，RNA 和蛋白迅速积累，但内化的 RNA 迅速下降到一个低水平设定点。值得注意的是，HCV 暴露于巨噬细胞会导致脂质和胆固醇增加，并激活胆固醇感知免疫调节肝 X 受体 (LXRs)。此外，我们提供的证据表明，巨噬细胞中 HCV RNA 的积累是通过吞噬受体发生的。这些结果表明，从感染的肝细胞释放的 HCV 刺激巨噬细胞中脂质的积累和 LXR 的激活，导致与 HCV 感染相关的慢性肝病中的代谢变化。我们的研究结果为巨噬细胞中与 HCV 感染相关的脂质代谢受损促进肝脂肪性肝炎和纤维化发展的机制提供了新的见解。
