Hepatic NK cells attenuate fibrosis progression of non-alcoholic steatohepatitis in dependent of CXCL10-mediated recruitment

Background & Aims Non-alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. The precise role of NK cells in the progression of NASH has yet to be elucidated. Methods Using methionine- and choline-deficient diets (MCD)-induced NASH model, the role of NK cells was identified in WT mice compared with conventional NK cell-deficient Nfil3(-/-) mice. Results After 8 weeks of MCD treatment, NASH was induced as shown by the significant macrovesicular steatosis, necro-inflammation and fibrosis in the liver of WT B6 mice. In MCD-treated WT B6 mice, the number of NK cells was markedly increased in the liver, but decreased in the spleen. Intrahepatic NK cells exhibited high levels of activation, as evidenced by the expression of CD107a and cytokine production of IFN-gamma, TGF-beta and IL-10. Lower expression levels of Ki67 indicated a reduction in the proliferation of intrahepatic NK cells after MCD treatment. Increased expression of CXCL10 in the liver early after MCD treatment led to the increased recruitment of CXCR3(+) NK cells into the liver. The MCD-treated Nfil3(-/-) mice showed similar levels of TG and macrovesicular steatosis, thus more inflammatory infiltration and increased collagen deposition in the liver. Furthermore, the depletion of NK cells during MCD-induced NASH caused a significant increase in the infiltration of monocyte-derived macrophages (MoMFs) particularly Ly6C(lo) subsets towards M2. Conclusions Intrahepatic NK cells, recruited through CXCL10-CXCR3 interaction, play a protective role against the fibrosis progression in NASH, which provide us with a better understanding of the immunopathogenesis of NASH.