Non-alcoholic fatty liver disease (
NAFLD) is a major cause of morbidity and mortality in developed countries, resulting in
steatohepatitis (NASH),
fibrosis and eventually
cirrhosis. Modulating inflammatory mediators such as
chemokines may represent a novel therapeutic strategy for
NAFLD. We recently demonstrated that the
chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling
inflammation in experimental
NAFLD. In this study, we first investigated human biopsies (n = 20), confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive
NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels) in human
NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in
NAFLD, using mouse models of acute
carbon tetrachloride (CCl4)- and chronic
methionine-
choline-deficient (MCD) diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory
cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced
fatty liver degeneration upon MCD diet, as assessed by hepatic
triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of
NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver
inflammation and
steatohepatitis.