title: Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation.
abstract: Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies.
authors.affiliation: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: D T
authors.initials: DT
authors.lastname: Reid
authors.affiliation: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Laboratorio de Inmunología Experimental y Regulación de la Inflamación Hepato-intestinal, UBIMED, FES Iztacala, UNAM, Mexico.
authors.forename: J L
authors.initials: JL
authors.lastname: Reyes
authors.affiliation: Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: B A
authors.initials: BA
authors.lastname: McDonald
authors.affiliation: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Vo
authors.affiliation: Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.|Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: Reimer
authors.affiliation: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Eksteen
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015415:Biomarkers; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016000:Cluster Analysis; D004032:Diet; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007113:Immunity, Innate; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008111:Liver Function Tests; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome
chemical_list: D015415:Biomarkers