ASPP2 enhances hepatic inflammation through exosome CD40L release derived from hepatocyte in alcoholic liver disease

Abstract ASPP2 plays an important role in regulating hepatic inflammation, but the mechanism has been unclear. Recent studies found that damaged hepatocytes can activate macrophages through releasing exosomes. Although there is no report that ASPP2 can regulate exosome release, some evidence suggests that ASPP2 may participate in exosome release by autophagy. Compared to wild type mice fed by EtOH diet, conditional ASPP2 gene knock out (ASPP2 ALB−/−) mice fed by EtOH diet showed decreased hepatic steatosis and inflammation. ASPP2 high expression promotes the exosome CD40L release in alcohol induction and vice versa. The expression of TNF- α, IL-1 β, IL-6 were increased in THP1 cells treated with exosome derived from 7702 cells with ASPP2 upregulation and vice versa. CD40L knockdown in hepatocytes reversed activated effect of ASPP2 on macrophages through exosomes CD40L derived from hepatocytes. ASPP2 enhanced exosome CD40L release through RAS-mTORC1-autophagy pathways in hepatocytes in alcohol induction. Compared to normal controls, the expression of ASPP2, TNF- α, IL-1 β, IL-6 in liver tissue and exosome CD40L in plasma increased significantly in patients with alcoholic liver cirrhosis. ASPP2 enhances hepatic inflammation and macrophages activation through exosome CD40L release from hepatocyte which is regulated by RAS-mTORC1-autophagy pathways in alcoholic liver disease.