Involvement of up-regulated CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in endotoxin-induced lethal liver injury via regulation of T-cell recruitment and adhesion.

A murine model of endotoxin-induced lethal liver injury induced by Mycobacterium bovis BCG plus lipopolysaccharide (LPS) has been widely accepted and used. It has been reported that T cells play an important role in the pathogenesis of liver damage in this model. However, the precise mechanisms involved in regulation of the trafficking of effector T cells need to be elucidated. In the present study, we first reported that CXCL16/SR-PSOX (CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), a chemokine containing both membrane-anchored and soluble forms, was strongly up-regulated and predominantly distributed in the vascular endothelium in the injured liver tissue in the model. The secretory and membrane-anchored CXCL16/SR-PSOX functioned as a chemokine and an adhesive molecule, respectively, to attract T cells to a tumor necrosis factor alpha-activated endothelial cell line (SVEC) in vitro. To further identify the pathophysiological roles of CXCL16/SR-PSOX in the liver injury, the anti-CXCL16 antibody was administered to the BCG-primed mice before LPS challenge in vivo. Significant protection effects were observed with 70% of mice regarding lethality, the massive necrosis in the liver was reduced, and the intrahepatic infiltrating T cells were significantly inhibited. Taken together, these findings strongly suggest that functional CXCL16/SR-PSOX, as both a chemokine and an adhesion molecule, may be involved in the pathogenesis of the endotoxin-induced lethal liver injury via recruitment and adhesion of activated T cells to the vascular endothelium.