SummaryMechanisms associated with the progression of simple steatosis to nonalcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (Tregs) play a critical role in regulating inflammatory processes in nonalcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose Treg-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.

T cell immunoglobulin and mucin domain-3 (Tim-3) is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. Little is known, though, about the function of Tim-3/Gal-9 signaling in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) mediated by hepatic natural killer T (NKT) cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti IL-15R/IL-15 mAb, recombinant IL-15, α-galactosylceramide and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflected cell proliferation, activation, cytokine production and apoptosis were analyzed. Liver histology, steatosis grade and hepatic triglyceride content were also evaluated. In the liver, Tim-3+ NKT cells are in an activated state and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3 expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cells funtion. In summary, the Tim-3/Gal-9 signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation induced apoptosis and secondary proliferation and thus contribute to the pathogenesis of NAFLD.