Thereby emerging as potential attractive targets for future therapeutic approaches. Work from our laboratory has recently identified a yet unrecognized pathway promoting inflammation in experimental steatohepatitis in mice. Using mice either deficient for the chemokine receptor CXCR6 or transgenic for a fluorescent protein in one of the CXCR6 alleles, the accumulation of natural killer T cells was identified as a rapid response to hepatocyte injury. Cxcr62/2 mice lacking type-I NKT cells were protected against acute- and chronic liver failure in two independent models of liver fibrosis, showed significantly attenuated hepatic inflammation and reduced levels of pro-inflammatory cytokines like tumor necrosis factor, monocyte chemoattractant protein-1 and interferon-c. The adoptive transfer of wildtype NKT cells into Cxcr6-deficient mice in a model of steatohepatitis restored inflammation and liver fibrosis. Our experimental data indicated that hepatic NKT cells specifically utilize its receptor CXCR6 for the rapid accumulation in injured livers, where they produce and release cytokines like interleukin 4 and IFNc that act on macrophages and possibly other hepatic cell compartments to initiate and perpetuate inflammation. We thus reasoned that inhibiting the cognate ligand for CXCR6, CXCL16, might hold therapeutic potential in steatohepatitis. Whereas in human inflamed livers CXCR6 is expressed by CD4 as well as CD8 T cells, NK cells and NKT cells the chemokine CXCL16 exists in a soluble and transmembrane form and is expressed by liver sinusoids, possibly allowing NKT cells to patrol hepatic vessels. CXCL16 is also expressed by hepatic macrophages, likely favoring interactions between NKT and Kupffer cells. Importantly, CXCL16 expression is up-regulated in acute or chronic liver injury in mice, but also in chronic liver diseases in humans. In this study, we investigated the pharmacological inhibition of CXCL16 using a monoclonal antibody as a novel therapeutic approach in experimental steatohepatitis in mice. Non-alcoholic fatty liver disease is a raising health burden in Western countries, which affect about 30% of the general adult population, is associated with an increased mortality and promote several medical complications like hepatocarcinogenesis in humans. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. Moreover, lipotoxic mediators and danger signals activate the hepatic macrophage pool, mainly Kupffer cells, which are critical for the initiation and perpetuation of the inflammatory response and release several inflammatory mediators. Such mediators, mainly cytokines and chemokines, attract inflammatory cells and activate parenchymal as well as non-parenchymal liver cells during NAFLD progression. In our study, we provide experimental Reversine evidence that interfering with the CXCR6-CXCL16 pathway might hold therapeutic potential in NAFLD. The administration of an anti-CXCL16 antibody blocked the rapid accumulation of patrolling hepatic NKT cells.