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Hepatology. 2013 Jan;57(1):331-8. doi: 10.1002/hep.26049.

Roles of hepatocyte and myeloid CXC chemokine receptor-2 in liver recovery and regeneration after ischemia/reperfusion in mice.

Author information

1
Department of Surgery, University of Cincinnati, Cincinnati, OH 45267, USA.

Abstract

Previous studies have demonstrated the significance of signaling through the CXC chemokine receptor-2 (CXCR2) receptor in the process of recovery and regeneration of functional liver mass after hepatic ischemia/reperfusion (I/R). CXCR2 is constitutively expressed on both neutrophils and hepatocytes; however, the cell-specific roles of this receptor are unknown. In the present study, chimeric mice were created through bone marrow transplantation (BMT) using wild-type and CXCR2-knockout mice, yielding selective expression of CXCR2 on hepatocytes (Hep) and/or myeloid cells (My) in the following combinations: Hep+/My+; Hep-/My+; Hep+/My-; and Hep-/My-. These tools allowed us to assess the contributions of myeloid and hepatocyte CXCR2 in the recovery of the liver after I/R injury. Flow cytometry confirmed the adoption of the donor phenotype in neutrophils. Interestingly, Kupffer cells from all chimeras lacked CXCR2 expression. Recovery/regeneration of hepatic parenchyma was assessed by histologic assessment and measurement of hepatocyte proliferation. CXCR2(Hep+/My+) mice showed the least amount of liver recovery and hepatocyte proliferation, whereas CXCR2(Hep-/My-) mice had the greatest liver recovery and hepatocyte proliferation. CXCR2(Hep+/My-) mice had enhanced liver recovery, with hepatocyte proliferation similar to CXCR2(Hep-/My-) mice. Myeloid expression of CXCR2 directly regulated CXC chemokine expression levels after hepatic I/R, such that mice lacking myeloid CXCR2 had markedly increased chemokine expression, compared with mice expressing CXCR2 on myeloid cells.

CONCLUSION:

The data suggest that CXCR2 on myeloid cells is the predominant regulator of liver recovery and regeneration after I/R injury, whereas hepatocyte CXCR2 plays a minor, secondary role. These findings suggest that myeloid cell-directed therapy may significantly affect liver regeneration after liver resection or transplantation.

PMID:
22961770
PMCID:
PMC3540195
DOI:
10.1002/hep.26049
[Indexed for MEDLINE]
Free PMC Article

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