METHODS:We investigated the role of IL-1β in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model.

RESULTS:Here, liver steatosis was accompanied by notably increased invariant NKT (iNKT) cell numbers and activation, and iNKT-deficient Jα18-/-mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1β were required for the hepatic iNKT accumulation, as blocking IL-1β signaling with a recombinant interleukin-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β in Kupffer cells by nanoparticle-encapsulated siRNA obviously inhibited hepatic iNKT cell accumulation and activation as well as amelioration of alcoholic fatty liver, and IL-1β over-expression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1β correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol-exposed wild-type(WT) mice, and NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells.

CONCLUSIONS:Kupffer cell-derived IL-1β, produced after alcohol-induced NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.

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