Spliceosome-Associated Protein 130 Exacerbates Alcohol-Induced Liver Injury by Inducing NLRP3 Inflammasome-Mediated IL-1β in Mice.

Excessive alcohol consumption leads to chronic liver diseases. Macrophage-inducible C-type lectin (Mincle) is a C-type lectin receptor that recognizes spliceosome-associated protein 130 (SAP130) known as an endogenous ligand released from dying cells. The aim was to examine the role of Mincle-SAP130 in the pathogenesis of alcoholic liver disease. Alcohol-induced liver injury was induced in wild-type (WT) and Mincle knockout (KO) mice by using a chronic-binge ethanol-feeding model. Mincle KO mice showed significant lower hepatic steatosis, inflammation with neutrophil infiltration, and fibrosis compared with WT mice after alcohol feeding. In contrast, Mincle activation exacerbated alcohol-induced liver injury. Kupffer cells (KCs) are major sources of Mincle. IL-1β expression was significantly down-regulated in Mincle KO mice compared with that in WT mice after alcohol consumption. Interestingly, expression and production of IL-1β were significantly decreased in SAP130-treated KCs isolated from leucine-rich-containing family pyrin domain containing-3-deficient mice compared with those in WT KCs. Such results were also observed in cells treated with SAP130 plus Syk inhibitor. Furthermore, infiltration of invariant natural killer T cells was decreased in livers of Mincle KO mice. Finally, inhibition of Syk signaling ameliorated alcohol-induced liver injury. Collectively, these results demonstrated that interaction between Mincle and SAP130 may promote the progression of alcoholic liver disease by IL-1β production in KCs and consequently increase inflammatory immune cell infiltration.

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