Inhibition of P2Y₆ receptor expression in Kupffer cells alleviates alcoholic steatohepatitis in mice

Inflammation plays an important role in the progression of alcohol-related liver disease (ALD). UDP-P2Y₆ signaling is involved in many human diseases. The purinergic P2Y₆ receptor, an important regulator of inflammation and phagocytosis, has attracted attention, but its role in alcoholic steatohepatitis remains unclear. Here, we found that P2Y₆ levels were significantly elevated in Kupffer cells in the livers of mice with alcoholic steatohepatitis and ethanol (EtOH)-induced RAW264.7 cells. In this study, mice with alcoholic steatohepatitis were intraperitoneally injected with MRS2578, a specific inhibitor of the P2Y₆ receptor, and P2Y₆ was silenced in EtOH-induced RAW264.7 cells. We found a marked improvement in steatosis and inflammation in the livers of mice with alcoholic steatohepatitis and EtOH-induced RAW264.7 cells. However, P2Y₆ activation in vivo and overexpression in vitro showed contrasting results. In addition, the expression of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK), a phosphorylated protein in the p38 MAPK signaling pathway, was significantly altered after P2Y₆ silencing or overexpression in vitro. P2Y₆ can induce the activation of the p38 MAPK signaling pathway by mediating the calcium influx, whereas inhibition of the expression of P2Y₆ can block the inflammatory process to some extent and thus improve the inflammatory response. The results of this study suggested that targeting P2Y₆ signaling may be a potentially effective strategy for the treatment of alcoholic steatohepatitis.