Role Of Innate Immune Cells In Alcoholic Liver Disease

Chronic excessive alcohol consumption leads to alcoholic fatty liver, then develops into a spectrum of alcoholic liver disease(ALD), including alcoholic hepatitis, fibrosis, cirhosis, and even hepatocellular carcinoma. The mechanisms underlying the formation of ALD are comprehensive and poly factorial, involving the interaction and crosstalk of multiple components and signaling molecules, including a variety of cells, cytokines, complements and transcription factors. Apart from the critical roles in natural defenses against pathogens and tumor tansformation, liver innate immunity also participates in regulating liver injury and repairing liver fibrosis. Alcohol consumption can accelerate liver inflammation and fibrosis not only by promoting the production of ROS and proinflammatory cytokine TNF-a in Kupffer cells, but by inhibiting the anti-fibrosis activities of NK/IFN-γ. However, the roles of NKT cells, which play vital roles in the liver innate immunity and act as a critical link between innate and adaptive immunity, are still controversial in ALD. The current study preliminarily investigated the important influence of NKT cells in the pathogenesis of ALD and the interactive mechanisms between NKT cells and Kupffer cells or NK cells, through the establishment of a chronic-binge ethanol feeding murine model.The main results of current studies including the following two aspects:1. Invariant NKT cells promote chronic-plus-binge alcoholic steatohepatitis depending on interleukin-lp in mice In a chronic plus single-binge ethanol consumption mouse model, we found that liver steatosis was accompanied by notably increased invariant NKT (iNKT) cell numbers and activation, and iNKT-deficient Jα18KO mice developed less alcohol-induced steatosis than control mice. Kupffer cells and IL-1β were required for this hepatic iNKT accumulation, as blocking IL-1β signaling with a recombinant interleukin-1receptor antagonist (IL-Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β in Kupffer cells by nanoparticle-encapsulated siRNA inhibited hepatic iNKT cell accumulation and activation as well as ameliorated alcoholic fatty liver. Moreover, IL-1β overexpression in hepatocytes was sufficient to partially compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1β correlated with elevated expression of the NLRP3inflammasome components NLRP3, ASC, and cleaved caspase-1in Kupffer cells purified from ethanol-exposed wild-type(WT) mice, and NLRP3deficiency phenocopied the attenuated alcoholic steatosis observed after Kupffer cell depletion, with only a minor increase in hepatic NKT cells.Conclusions:Kupffer cell-derived IL-1β produced downstream of alcohol-induced NLRP3activation recruits and activates hepatic iNKT cells, subsequently inducing alcoholic liver injury.2. Inhibition of NK cell activity by invariant NKT cell-derived interluekin-10aggravates alcoholic steatohepatitis. In the chronic-binge model, the numbers of hepatic NK cells in WT mice gradually decreased after the gavage, showing dynamics opposite to NKT cells. However, in iNKT cell-deficient Ja18KO mice, the NK cell numbers and functions including the abilities of degranulation and IFN-y production were increased notably associated with alleviated alcohol induced liver steatosis and injury, and depleting NK cells by AsGM1treatment obviously promoted alcoholic liver steatosis and damage. In addition, adoptive transfer of iNKT cells into Jα18KO mice or respectively transfer hepatic MNCs from WT mice or Jα18KO mice into Ragl KO mice, further conforming that iNKT cells aggravated alcoholic steatohepatitis by inhibiting NK cell numbers and functions. Mechanistic studies revealed that iNKT cell-derived IL-10was the key mediator inducing the inhibition of NK cells, as the NK cell numbers and functions were restored in IL-10KO mice or in recombinant IL-10treated Jα18KO mice.Conclusions:alcohol feeding induced accumulation and activation of hepatic iNKT cells derived IL-10, inhibits NK cell numbers and functions in the liver, subsequently promotes the pathogenesis of alcoholic steatohepatosis.In summary, the production of IL-1β downstream of alcohol consumption induced NLRP3activation in Kupffer cells recruits and activates hepatic iNKT cells, which inhibits the numbers and functions of NK cells in the liver, and subsequently promotes the development of alcoholic liver steatosis and injury.