Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice

Background & Aims: It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1 beta release in alcoholic liver injury; however, how IL-1 beta promotes liver injury remains unclear. Methods: We investigated the role of IL-1 beta in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model. Results: Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient J alpha 18(-/)-mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1 beta were required for the hepatic iNKT accumulation, as either blocking IL-1 beta signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1 beta in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1b overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1 beta correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol-exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells. Conclusions: After alcohol-exposure Kupffer cell-derived IL-1 beta triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.