Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis

PLoS One. 2016 Feb 19;11(2):e0149783. doi: 10.1371/journal.pone.0149783. eCollection 2016.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Choline / administration & dosage
  • Diet
  • Disease Models, Animal
  • Hepatitis / immunology
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Interleukin-17 / metabolism*
  • Macrophages / immunology
  • Male
  • Methionine / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology

Substances

  • Il17a protein, mouse
  • Il17f protein, mouse
  • Il17ra protein, mouse
  • Interleukin-17
  • Receptors, Interleukin-17
  • Methionine
  • Choline