Suppression of Natural Killer Cell Activity by Regulatory NKT10 Cells Aggravates Alcoholic Hepatosteatosis.

Kele Cui,Guoxiu Yan,Haiming Wei,Rui Sun,Xiaodong Zheng,Li Bai,Zhigang Tian

doi:10.3389/fimmu.2017.01414

Abstract

We and others have found that the functions of hepatic natural killer (NK) cells are inhibited but invariant NKT (iNKT) cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-γ (IFN-γ) protected against ethanol-induced liver steatosis, as both wild-type (WT) mice treated with anti-asialo GM1 antibody and IFN-γ-deficient GKO mice developed more severe alcoholic fatty livers. As expected, IFN-γ could directly downregulate lipogenesis in primary hepatocytes in vitro. On the contrary, iNKT cell-deficient Jα18−/− or interleukin-10 (IL-10)−/− mice showed fewer alcoholic steatosis, along with the recovered number and IFN-γ release of hepatic NK cells, and exogenous IL-10 injection was sufficient to compensate for iNKT cell deficiency. Furthermore, NK cell depletion in Jα18−/− or IL-10−/− mice caused more severe hepatosteatosis, implying NK cells are the direct effector cells to inhibit liver steatosis. Importantly, adoptive transfer of iNKT cells purified from normal but not IL-10−/− mice resulted in suppression of the number and functions of NK cells and aggravated alcoholic liver injury in Jα18−/− mice, indicating that IL-10-producing iNKT (NKT10) cells are the regulators on NK cells. Conclusion: Ethanol exposure-triggered NKT10 cells antagonize the protective roles of NK cells in alcoholic hepatosteatosis.

Highlights

Excessive alcohol consumption is a major etiologic factor in chronic liver disease worldwide
We demonstrated that natural killer (NK) cells play essential protective roles against liver steatosis through the IFN-γ-induced downregulation of fat metabolism-associated genes in hepatocytes in a chronic plus single-binge ethanol consumption mouse model, which can be inhibited by a IL-10-producing invariant NKT (iNKT) cell subset, suggesting an interplay between NK cells and NKT10 cells during alcoholic liver disease (ALD) pathogenesis
We observed that hepatic steatosis progressively increased and that liver damage was gradually alleviated in the antiasialo GM1 (AsGM1)-treated mice at 3, 6, and 9 h after ethanol gavage compared with control mice, confirming that NK cells exert different functions in liver steatosis and injury (Figure 2)

Summary

Introduction

Excessive alcohol consumption is a major etiologic factor in chronic liver disease worldwide. The mechanisms underlying the formation of alcoholic liver disease (ALD) are complex and polyfactorial and involve alcohol metabolite-induced hepatotoxicity, oxidative stress, and the overactivity or dysregulation of the innate immune system caused liver damage [1]. As a key component of innate immunity in the liver, NK cells play important roles in antiviral infection and tumor immunosurveillance through their natural cytotoxicity, such as degranulation to directly kill target cells or the secretion of large amounts of cytokines, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, which act on other immune cells [3,4,5,6]. Little is known about the roles of NK cells in the early stages of ALD, such as alcoholic hepatosteatosis

Methods

Results

Conclusion