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

Abstract

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‐γ, TGF‐β 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 Ly6Clo 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.

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…In addition, transcriptional analyses revealed a dysregulation in extracellular matrix remodeling and hepatic stellate cell activation in response to MCD, but not an atherogenic diet [41]. Altogether, these data pointed towards a more severe form of NASH in MCD mice [41], which was in line with previous studies showing that MCD triggered extensive hepatic inflammation in rats [43] and mice [44][45][46] within a very short time frame. To overcome the lack of severe hepatic fibrosis often observed in preclinical models, mice are commonly fed MCD [47] or a diet low in/deficient for choline (CD) [48].…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…136 cNK cells were found to be recruited into the liver in a CXCL10dependent manner, and they prevented NASH progression to fibrosis through the production of IFN-γ, which regulated macrophage polarization toward M1-like macrophages. 137,138 IL-15 signaling in hepatocytes upregulated the expression of chemokines CXCL10, CCL2, and CCL5, accounting for the recruitment of immune cells, including NK cells, into the liver. 139 In the obese liver, NK cells converted toward ILC1-like cells with increased CD200r1 and CD49a expression, partially mediated by enhanced TGF-β, which showed protective roles with reduced cytotoxicity in the progression of NASH.…”

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

“…However, increased number of CD49b + NKp46 + cNK cells were demonstrated to prevent MCD-induced NASH progression to fibrosis by polarizing macrophage toward M1-like phenotypes, which depended on their production of IFN-γ but not granzyme-mediated cytotoxicity ( 62 ). Increased expression of CXCL10 early after MCD treatment accounted for the recruitment of cNK cells into the liver, resulting in the attenuated inflammatory infiltration of CD45 + CD11b hi F4/80 int monocyte-derived macrophages (MoMFs) particularly Ly6C lo subsets skewed toward M2 ( 63 ). The upregulation of expression levels of chemokines including CXCL10, CCL2 and CCL5 was demonstrated to be dependent on IL-15 signaling in response to HFD in hepatocytes, which accounted for the recruitment of immune cells ( 64 ).…”