CXCL16 silencing alleviates hepatic ischemia reperfusion injury during liver transplantation by inhibiting p38 phosphorylation

Abstract

CXC chemokine ligand 16 (CXCL16) has been reported to exacerbate acute kidney injury induced by ischemia-reperfusion (IR). This study aimed to investigate the probable role of CXCL16 in hepatic IR injury during liver transplantation. The expression patterns of CXCL16 and its receptor CXC chemokine receptor 6 (CXCR6) were detected in mouse models of IR injury during liver transplantation and cell models of oxygen-glucose deprivation and reoxygenation (OGD/R)-induced hepatocyte injury using RT-qPCR, Western blot analysis and ELISA. CXCL16 expression was silenced in AML12 cells exposed to OGD/R conditions to determine the role of CXCL16 in cell apoptosis and injury. After treatment with CXCL16 and a p38 phosphorylation inhibitor, SB203580, we examined whether CXCL16 regulated p38 phosphorylation to impact hepatocyte injury. To verify the effects of CXCL16 and p38 phosphorylation in vivo, CXCL16 was silenced and p38 phosphorylation was activated in IR-treated mice. CXCL16 and CXCR6 were highly expressed in mouse models of IR injury and cell models of OGD/R-induced hepatocyte injury. Silencing of CXCL16 in AML12 cells resulted in diminished CXCR6 expression and alleviated OGD/R-exposed cell injury. CXCL16 treatment in AML12 cells brought about increased protein expressions of CXCR6 and p38 phosphorylation and elevated apoptosis rate of hepatocytes. Inhibition of p38 phosphorylation neutralized CXCL16-induced apoptosis of AML12 cells. Furthermore, CXCL16 knockdown in vivo relieved hepatic injury, which was reversed by activation of p38 phosphorylation. Taken together, silencing of CXCL16 might protect against IR injury during liver transplantation by reducing p38 phosphorylation, highlighting the potential of CXCL16 as a promising target for treatment against hepatic IR injury.