title: Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury.
abstract: Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Shi
authors.initials: S
authors.lastname: Yue
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Haoming
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Ronald W
authors.identifier: 0000-0001-8157-1531
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095; and yzhai@mednet.ucla.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007109:Immunity; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D015427:Reperfusion Injury / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; D007093:Imidazoles; D007211:Indoles; C490620:Ralbp1 protein, mouse; C507699:necrostatin-1; D004002:Clodronic Acid