Alcoholic liver disease (ALD) is characterized by increased hepatic lipid accumulation (steatosis) and inflammation with increased expression of proinflammatory cytokines. Two of these cytokines, interleukin-1β (IL-1β) and IL-18, require activation of caspase-1 via members of the NOD-like receptor (NLR) family. These NLRs form an inflammasome that is activated by pathogens and signals released through local tissue injury or death. NLR family pyrin domain containing 3 (Nlrp3) and NLR family CARD domain containing protein 4 (Nlrc4) have been studied minimally for their role in the development of ALD. Using mice with gene targeted deletions for Nlrp3 (Nlrp3？/？) and Nlrc4 (Nlrc4？/？), we analyzed the response to chronic alcohol consumption. We found that Nlrp3？/？ mice have more severe liver injury with higher plasma alanine aminotransferase (ALT) levels, increased activation of IL-18, and reduced activation of IL-1B. In contrast, the Nlrc4？/？ mice had similar alcohol-induced liver injury compared to C57BL/6J (B6) mice but had greatly reduced activation of IL-1β. This suggests that Nlrp3 and Nlrc4 inflammasomes activate IL-1β and IL-18 via caspase-1 in a differential manner. We conclude that the Nlrp3 inflammasome is protective during alcohol-induced liver injury. 1. Introduction Alcoholic liver disease (ALD) represents a variety of clinical and morphological changes that range from steatosis to inflammation and necrosis (alcoholic hepatitis) to progressive fibrosis (alcoholic cirrhosis) [1]. Most chronic heavy drinkers exhibit steatosis characterized by a greater amount of macrovesicular fat content than microvesicular fat. In addition, hepatocyte ballooning degeneration with mixed lobular inflammation is evident [2, 3]. Patients with ALD also have elevated serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which is evidence of liver injury. The severity of disease is not always correlated with the amount of alcohol consumed. In fact, most long-term heavy drinkers develop steatosis, but only 20–30% of these patients develop hepatitis, and less than 10% will progress to cirrhosis [4–6]. Activation of the immune system plays a critical role in the pathogenesis of ALD. Presently the current hypothesis for ethanol-induced liver injury proposes that ethanol results in leakage of bacterial products from the gut. Furthermore, chronic ethanol exposure alters the jejunal microflora leading to an increase in Gram-negative bacteria. Together these alterations cause an increase in circulating lipopolysaccharide (LPS) from
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