The Balance between IL-17 and IL-22 produced by liver infiltrating T helper cells critically controls NASH development in mice

The mechanisms responsible for the evolution of steatosis toward non-alcoholic steato-hepatitis (NASH) and fibrosis are not completely defined. This study evaluated the role of CD4(+) T-helper (Th) cells in this process. We analyzed the infiltration of different subsets of CD4(+)Th cells in C57BL/6 mice fed with a methione-choline deficient (MCD) diet, which is a model reproducing all phases of human NASH progression. There was an increase in Th17 cells at the beginning of NASH development and at the NASH/fibrosis transition, whereas levels of Th22 cells peaked between the first and the second expansion of Th17 cells. An increase in the production of IL-6, TNFa, TGFβ and CCL20 accompanied the changes in Th17/22 cells. Livers of IL-17(-)/(-) mice were protected from NASH development and characterized by an extensive infiltration of Th22 cells. In vitro , IL-17 exacerbated the JNK-dependent mouse hepatocyte lipotoxicity induced by palmitate. IL-22 prevented lipotoxicity through phosphatidylinositol-3-kinase-mediated inhibition of JNK but did not play a protective role in the presence of IL-17, which upregulated the phosphatidylinositol-3-kinase/Akt inhibitor PTEN. Consistently, livers of IL-17(-)/(-) mice fed with the MCD diet displayed decreased activation of JNK, reduced expression of PTEN and increased phosphorylation of Akt compared to livers of wild type mice. Hepatic infiltration of Th17 cells is critical for NASH initiation and development of fibrosis in mice, and reflects an infiltration of Th22 cells. Th22 cells are protective in NASH, but only in the absence of IL-17. These data strongly support the potentiality of clinical applications of IL-17 inhibitors that can prevent NASH by both abolishing the lipotoxic action of IL-17 and allowing IL-22-mediated protection.