title: CCL2-CCR2 signaling promotes hepatic ischemia/reperfusion injury.
abstract: Liver ischemia/reperfusion (I/R) injury is a type of uncontrolled inflammatory cascade in which neutrophils, an early infiltrating immune cell population, elicit significant tissue damage. However, the precise mechanism for neutrophil recruitment and infiltration remains to be fully characterized.
  
  
  
  A hepatic partial I/R model was reproduced in wild-type, CCL2(-/-) and CCR2(-/-) mice. Tissue damage was evaluated by serum enzyme analysis, hematoxylin-eosin staining, and cytokine production measurement. Mobilization of neutrophils from the bone marrow and subsequent infiltration into the liver were measured by flow cytometry. C-C motif chemokine receptor 2 (CCR2) expression on neutrophils and C-C motif chemokine ligand 2 (CCL2) chemotaxis were measured using flow cytometry. The cellular source of CCL2 in the liver was determined by deleting specific cell groups and performing intracellular staining.
  
  
  
  Liver damage was ameliorated, and neutrophil recruitment and accumulation were decreased in both CCL2(-/-) and CCR2(-/-) mice compared with wild-type mice. Neutrophils displayed upregulated expression of CCR2 during I/R, and these cells were required for CCL2-induced chemotaxis. Depletion of Kupffer cells protected the liver from I/R injury. Furthermore, genetic ablation of CCL2 reduced liver injury, as demonstrated by decreases in the levels of alanine aminotransferase and aspartate aminotransferase and subsequent reductions in neutrophil recruitment and accumulation.
  
  
  
  Kupffer cells secrete CCL2 to promote CCR2-expressing neutrophil recruitment from the bone marrow and subsequent infiltration into the liver during I/R. These findings reveal a novel pro-inflammatory role of cell-mediated CCL2-CCR2 interactions during this sterile insult.
authors.affiliation: Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Junbin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Vascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangcy@tjh.tjmu.edu.cn.
authors.forename: Congyi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhangjinxiang@hust.edu.cn.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D048550:Hepatic Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2
keywords: CCL2; CCR2; Ischemia/reperfusion; Kupffer cells; Neutrophils