Laboratory Animal Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
Center for Molecular and Clinical Immunology, Chang Gung University, Chang Gung, Taiwan.
Sci Rep. 2017 Jun 16;7(1):3698. doi: 10.1038/s41598-017-03956-7.
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.
CCL5/RANTES，一种趋化因子，可趋化骨髓细胞，它会被肝脏缺血再灌注损伤（IRI）诱导。通过 CCL5 免疫耗竭、Met-CCL5 的拮抗竞争和重组鼠 CCL5（rmCCL5）的治疗，研究了 CCL5 在肝 IRI 中的作用。CCL5 的耗竭或抑制可减轻肝 IRI 的严重程度，而 rmCCL5 治疗则加重了肝 IRI，表现为血清丙氨酸氨基转移酶（ALT）和组织髓过氧化物酶（MPO）水平升高。此外，CCL5 敲除（CCL5-KO）小鼠的 IRI 严重程度低于野生型（WT）小鼠，血清 ALT 水平、肝内 MPO 活性和组织病理学均有所下降。骨髓移植（BMT）研究表明，CCL5 加重肝 IRI 需要骨髓细胞和组织细胞。肝再灌注后肝浸润白细胞亚群的特征表明，在再灌注早期，CCL5-KO 小鼠与 WT 对照相比，CD11b+细胞是唯一明显减少的细胞群。CCL5 招募 CD11b+细胞在再灌注早期的作用通过体外转染小室迁移实验得到了验证，该实验中，早期再灌注后，肝裂解物可趋化鼠原代巨噬细胞（以其广泛表达的 CD11b 为特征）迁移。综上所述，我们的结果表明，CCL5 趋化巨噬细胞引发了一系列早期事件，导致肝 IRI 的炎症加重。
