Hepatocyte signaling through CXC chemokine receptor-2 is detrimental to liver recovery after ischemia/reperfusion in mice

CXC chemokines and their receptor, CXC chemokine receptor-2 (CXCR2), are important components of the hepatic inflammatory response to ischemia/reperfusion (I/R). However, direct effects of CXC chemokines on hepatocytes during this response have not been studied. Wild-type and CXCR2(-/-) mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 96 hours of reperfusion. CXCR2(-/-) mice had significantly less liver injury at all reperfusion times compared with wild-type mice. Early neutrophil recruitment (12 hours) was diminished in CXCR2(-/-) mice, but within 24 hours it was the same as that of wild-type mice. Hepatocyte proliferation and regeneration was accelerated in CXCR2(-/-) mice compared with wild-type mice. These effects were associated with increased activation of nuclear factor kappa B and signal transducers and activators of transcription-3, despite there being no difference in the expression of proliferative factors such as tumor necrosis factor alpha, interleukin-6, and hepatocyte growth factor. To establish whether the accelerated proliferation and regeneration observed in CXCR2(-/-) mice was due to effects on hepatocytes rather than just a generalized decrease in acute inflammatory injury, mice were treated with the CXCR2 antagonist, SB225002, after neutrophil recruitment and injury were maximal (24 hours after reperfusion). SB225002 treatment increased hepatocyte proliferation and regeneration in a manner identical to that observed in CXCR2(-/-) mice. Treatment of primary wild-type hepatocytes with macrophage inflammatory protein-2 revealed that low concentrations protected against cell death, whereas high concentrations induced cell death. These effects were absent in hcpatocytes from CXCR2(-/-) mice. Conclusion: Our data suggest that hepatocyte CXCR2 regulates proliferation and regeneration after I/R injury and reveal important differences in the role of this receptor in liver regeneration and repair induced under different conditions that may be related to ligand concentration.