TY - JOUR
T1 - CXCL10-Mediates Macrophage, but not Other Innate Immune Cells-Associated Inflammation in Murine Nonalcoholic Steatohepatitis
AU - Tomita, Kyoko
AU - Freeman, Brittany L.
AU - Bronk, Steven F.
AU - LeBrasseur, Nathan K.
AU - White, Thomas A.
AU - Hirsova, Petra
AU - Ibrahim, Samar H.
N1 - Funding Information:
This work was supported by the Mayo Clinic Center for Clinical and Translational Science (CCaTS), KL2 program KL2TR000136-09 (to SHI), a Pilot and Feasibility Award and the Optical Microscopy Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567) (to SHI), the Glenn Foundation for Medical Research and a generous gift from Robert and Arlene Kogod foundation (to NKL), American Liver Foundation (to PH), and the Mayo Clinic, Rochester, MN.
PY - 2016/6/28
Y1 - 2016/6/28
N2 - 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.
AB - 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.
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U2 - 10.1038/srep28786
DO - 10.1038/srep28786
M3 - Article
C2 - 27349927
AN - SCOPUS:84976393726
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 28786
ER -