Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury

Abstract

Aim Activation of hepatic stellate cells and development of chronic inflammation are two key features in the progression of hepatic fibrosis. We have shown that in vitro activated stellate cells increase their expression of CXCL 12 as well as the receptor CXCR 4 and that receptor engagement promotes a profibrogenic phenotype. Furthermore, injury promotes increased hepatic expression of CXCL 12 and a massive infiltration of CXCR 4‐expressing leukocytes, granulocytes and myeloid cells. The primary site of inflammatory cell accumulation is around the CXCL 12‐rich portal tracts and within fibrotic septae, indicating a role for CXCR 4 during injury. In order to characterize the relevance of the CXCR 4/ CXCL 12 chemokine axis during hepatic injury we inhibited the axis using AMD 3100, a CXCR 4 small molecule inhibitor, in models of chronic and acute liver injury. Methods Mice were subjected to acute and chronic CC l 4 liver injury with and without AMD 3100 administration. The degree of liver injury, fibrosis and the composition of the intrahepatic inflammatory response were characterized. Results Treatment of mice with AMD 3100 in the chronic CC l 4 model of liver injury led to an increase in hepatic inflammation and fibrosis with a specific increase in intrahepatic neutrophils. Furthermore, in an acute model of CC l 4 ‐induced liver injury, AMD 3100 led to an increase in the number of intrahepatic neutrophils and a trend towards worse necrosis. Conclusion Together, this data suggests that inhibition of the CXCR 4/ CXCL 12 chemokine axis is injurious through modulation of the hepatic inflammatory response and that this axis may serve a protective role in liver injury.