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.