Cell-Specific Regulatory Effects of CXCR2 on Cholestatic Liver Injury.

CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability, but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2 -/- mice were subjected BDL. CXCR2 chimeric mice were created to assess cell specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibitor. CXCR2 -/- mice had significant less liver injury than wild-type mice at 3 days and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2 -/- mice showed significantly less neutrophil accumulation in those injured area. CXCR2 Liver+/Myeloid+ and CXCR2Liver-/Myeloid- mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2 Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid+ , however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid- and CXCR2Liver-/Myeloid- ) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.