title: Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury.
abstract: The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF subsets. In this study, we used a murine model of acute liver injury induced by overdose of N-acetyl-p-aminophenol (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6C(hi) monocytes. The latter were recruited in a CCR2- and M-CSF-mediated pathway at the necroinflammatory phase and differentiated into ephemeral Ly6C(lo) MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray-based molecular profiling uncovered high similarity between steady-state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct prorestorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a prorestorative polarization manifested by unique expression of proangiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic, and molecular definition of liver-MF compartment following acute injury.
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Ehud
authors.initials: E
authors.lastname: Zigmond
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Shany
authors.initials: S
authors.lastname: Samia-Grinberg
authors.affiliation: Bioinformatics Unit, G.S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Eli
authors.initials: E
authors.lastname: Brazowski
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and.
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.affiliation: The Research Center for Digestive Tract and Liver Diseases, Sourasky Medical Center, Tel Aviv 64239, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and chenv@tlvmc.gov.il.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007728:Kupffer Cells / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000293:injuries / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen