Journal Article

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

Stankiewicz, Traci E., Shanmukhappa, Shiva K., Cappelletti, Monica, Moreno-Fernandez, Maria E., Divanovic, Senad, Giles, Daniel A., Iwakura, Yoichiro, Huppert, Stacey S., Dong, Chen

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Biology and Life Sciences / CD4 antigen / CD8 antigen / Choline / Choline - administration & dosage / Control / Development and progression / Diet / Disease Models, Animal / Fatty liver / Gastroenterology / Hepatitis / Hepatitis - immunology / Hepatitis - metabolism / Hepatitis - pathology / Hepatology / Homogenization / Hospitals / Immunology / Infiltration / Inflammation / Interleukin 17 / Interleukin-17 - metabolism / Laboratory animals / Ligands / Liver / Liver diseases / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - immunology / Male / Medicine / Medicine and Health Sciences / Methionine / Methionine - administration & dosage / Mice / Mice, Inbred C57BL / Non-alcoholic Fatty Liver Disease - immunology / Nutrition research / Obesity / Oxidation / Pathogenesis / Physiological aspects / Receptors, Interleukin-17 - metabolism / Rodents / Signal Transduction / Steatosis / T-Lymphocytes - immunology