title: Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis.
abstract: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Giles
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Moreno-Fernandez
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Traci E
authors.initials: TE
authors.lastname: Stankiewicz
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Cappelletti
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Huppert
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Shanmukhappa
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
mesh_terms: D000818:Animals; D002794:Choline / Q000008:administration & dosage; D004032:Diet; D004195:Disease Models, Animal; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C098680:Il17a protein, mouse; C515932:Il17f protein, mouse; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D008715:Methionine; D002794:Choline