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

It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1β release in alcoholic liver injury; however, how IL-1β promotes liver injury remains unclear.

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

Here, liver steatosis was accompanied by notably increased invariant natural killer T (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 either blocking IL-1β signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β 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-1β overexpression 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 mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells.

After alcohol-exposure Kupffer cell-derived IL-1β triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.