title: CXCL10-Mediates Macrophage, but not Other Innate Immune Cells-Associated Inflammation in Murine Nonalcoholic Steatohepatitis.
abstract: Nonalcoholic steatohepatitis (NASH) is an inflammatory lipotoxic disorder, but how inflammatory cells are recruited and activated within the liver is still unclear. We previously reported that lipotoxic hepatocytes release CXCL10-enriched extracellular vesicles, which are potently chemotactic for cells of the innate immune system. In the present study, we sought to determine the innate immune cell involved in the inflammatory response in murine NASH and the extent to which inhibition of the chemotactic ligand CXCL10 and its cognate receptor CXCR3 could attenuate liver inflammation, injury and fibrosis. C57BL/6J CXCL10(-/-), CXCR3(-/-) and wild type (WT) mice were fed chow or high saturated fat, fructose, and cholesterol (FFC) diet. FFC-fed CXCL10(-/-) and WT mice displayed similar weight gain, metabolic profile, insulin resistance, and hepatic steatosis. In contrast, compared to the WT mice, FFC-fed CXCL10(-/-) mice had significantly attenuated liver inflammation, injury and fibrosis. Genetic deletion of CXCL10 reduced FFC-induced proinflammatory hepatic macrophage infiltration, while natural killer cells, natural killer T cells, neutrophils and dendritic cells hepatic infiltration were not significantly affected. Our results suggest that CXCL10(-/-) mice are protected against diet-induced NASH, in an obesity-independent manner. Macrophage-associated inflammation appears to be the key player in the CXCL10-mediated sterile inflammatory response in murine NASH.
authors.affiliation: Division of Gastroenterology &Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Division of Gastroenterology &Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Freeman
authors.affiliation: Division of Gastroenterology &Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.affiliation: Department of Physical Medicine &Rehabilitation Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Department of Physical Medicine &Rehabilitation Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Division of Gastroenterology &Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.affiliation: Division of Gastroenterology &Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Samar H
authors.initials: SH
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000009:adverse effects; D005632:Fructose / Q000009:adverse effects; D007107:Immune System / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D009765:Obesity / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D002791:Cholesterol, Dietary; C485433:Cxcl10 protein, mouse; D004040:Dietary Carbohydrates; D005632:Fructose