The role of C5aR1-mediated hepatic macrophage efferocytosis in NASH

Abstract NAFLD has become the first major chronic liver disease in developed countries. 10-20% of NAFLD patients will progress to NASH, and up to 25% of NASH patients may develop cirrhosis within 10 years. Therefore, it is critical to find key factors that may treat this disease. Here, we identified C5aR1 as a highly-expressed gene in NASH model mice through analyzing GEO database and confirmed its higher expression in livers of NASH patients than that of NAFL patients. Meanwhile, we verified its positive correlation with patients’ serum ALT and AST levels. In vivo and in vitro experiments revealed that knocking down C5aR1 in liver significantly reduced liver weight ratio and serum ALT and AST levels and attenuated inflammatory cell infiltration and cell apoptosis in the liver of NASH mice as well as enhanced the efferocytotic ability of liver macrophages, suggesting that C5aR1 may play a crucial role in the efferocytosis of liver macrophages. Furthermore, we also found that the expression levels of NLRP3, caspase-1, IL-1β and other inflammation-related factors in the liver were significantly reduced. Our work demonstrates a potential mechanism of how C5aR1 deficiency protects against diet-induced NASH by coordinating the regulation of inflammatory factors and affecting hepatic macrophage efferocytosis.