IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Authors

  • Isaac T.W. Harley,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Traci E. Stankiewicz,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Daniel A. Giles,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Samir Softic,

    1. Division of Gastroenterology, Hepatology and Clinical Nutrition, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
    Current affiliation:
    1. Boston Children's Hospital, Division of Gastroenterology and Nutrition, Boston, MA 02115
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  • Leah M. Flick,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
    Current affiliation:
    1. Meridian Bioscience, Cincinnati, OH 45244
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  • Monica Cappelletti,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Rachel Sheridan,

    1. Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Stavra A. Xanthakos,

    1. Division of Gastroenterology, Hepatology and Clinical Nutrition, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Kris A. Steinbrecher,

    1. Division of Gastroenterology, Hepatology and Clinical Nutrition, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • R. Balfour Sartor,

    1. Departments of Medicine, Microbiology and Immunology, Division of Gastroenterology & Hepatology, University of North Carolina, Chapel Hill, NC
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  • Rohit Kohli,

    1. Division of Gastroenterology, Hepatology and Clinical Nutrition, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
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  • Christopher L. Karp,

    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
    Current affiliation:
    1. Bill & Melinda Gates Foundation, Seattle, WA 98102
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  • Senad Divanovic

    Corresponding author
    1. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and the University of Cincinnati College of Medicine, Cincinnati, OH
    • Address reprint request to: Senad Divanovic, Ph.D., Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, TCHRF - Location S, Room #S.5.409, 3333 Burnet Ave., Cincinnati, OH 45229-3039. E-mail: senad.divanovic@cchmc.org; fax: 513-636-5355.

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  • See Editorial on Page 1671

    Potential conflict of interest: Nothing to report.

  • Supported by an R01 DK099222, a Pilot Grant under NIH P30 DK078392, and a CCHMC Trustee Grant (to SD). I.T.W.H. received funding from NIH grants AI075159, HD07463, GM063483, and a Fellowship from the Albert J. Ryan Foundation. Gnotobiotic mice were supported by P40 OD010995, P30 DK34987 and the Crohn's and Colitis Foundation of America.

Abstract

Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA−/− mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. Conclusion: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839)

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