Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 331–338, January 2013
How to Cite
Van Sweringen, H. L., Sakai, N., Quillin, R. C., Bailey, J., Schuster, R., Blanchard, J., Goetzman, H., Caldwell, C. C., Edwards, M. J. and Lentsch, A. B. (2013), Roles of hepatocyte and myeloid CXC chemokine receptor-2 in liver recovery and regeneration after ischemia/reperfusion in mice. Hepatology, 57: 331–338. doi: 10.1002/hep.26049
Potential conflict of interest: Nothing to report.
This work was supported by the National Institutes of Health (grant nos.: DK56029 and AG025881; to A.B.L.).
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 7 SEP 2012 09:02AM EST
- Manuscript Accepted: 9 AUG 2012
- Manuscript Received: 30 APR 2012
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. CXCR2Hep+/My+ mice showed the least amount of liver recovery and hepatocyte proliferation, whereas CXCR2Hep−/My− mice had the greatest liver recovery and hepatocyte proliferation. CXCR2Hep+/My− mice had enhanced liver recovery, with hepatocyte proliferation similar to CXCR2Hep−/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. (HEPATOLOGY 2013)