C-C Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury

Chiou-Mei Lee,Yuan-Ji Day,Chia-Chih Liao,Hsin-Hsin Peng,Jiin-Tarng Liou,Polung Yang

doi:10.1038/s41598-017-03956-7

Abstract

CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5-aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI.

Highlights

Ischemia/Reperfusion injury (IRI) is a major concern of surgical procedures involving liver, especially major hepatic resection and liver organ transplantation, which subject hepatic tissues to ischemic conditions[1]
We have shown with Bone marrow transplantion (BMT) mice models that myeloid cells and tissue-derived CCL5 are both essential contribution in liver IR injury, and defective CCL5 expression resulted in impairment of leukocyte infiltration
We have shown that ATL146e, an agonist of A2AAR, alleviated hepatic ischemia/reperfusion injury (IRI) in conjunction with reduction of the expression levels of proinflammatory cytokines, in particular CCL514–16

Summary

Introduction

Ischemia/Reperfusion injury (IRI) is a major concern of surgical procedures involving liver, especially major hepatic resection and liver organ transplantation, which subject hepatic tissues to ischemic conditions[1]. The cerebral ischemia-reperfusion model in particular implicated that CCL5 derived from myeloid cells might at least partially contribute to reperfusion-induced inflammation, in addition to the chemotactic signal released by the injured tissues. We have shown with BMT mice models that myeloid cells and tissue-derived CCL5 are both essential contribution in liver IR injury, and defective CCL5 expression resulted in impairment of leukocyte infiltration. It is notable that mice with CCL5 deficiency exhibited significantly reduced macrophage recruitment during early reperfusion following 1 hr liver ischemia. These results show that CCL5 facilitates macrophage recruitment to the site of liver IRI, leading to pro-inflammatory inductions and subsequent injuries. CCL5 activity may represent a potential target for novel therapeutic strategies against ischemia-reperfusion damages during hepatic operations

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Conclusion