Alcohol abuse is a leading cause of morbidity and mortality worldwide. The deleterious effects of alcohol abuse on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. NLRP3 inflammasome is a multi-protein cytoplasmic complex that serves as pattern recognition receptor and has emerged as key mediator of inflammation, and cell death. The NLRP3 inflammasome senses damage- associated molecular patterns and induces secretion of IL-1? and IL-18 that may be destructive to tissues. We, and others, have recently shown that hepatic caspase 1 activation occurs during the development of ASH and nonalcoholic steatohepatitis (NASH) and this activation appears to be mediated through the NLRP3 inflammasome. These studies demonstrated that caspase 1 plays an important role in inflammation and fibrosis during ASH and NASH development while IL-1 receptor antagonist ameliorates ASH in mice. A role for NLRP3 inflammasome gain-of-function mutations was initially described in a group of rare autoinflammatory monogenic conditions. Subsequently, multiple gene polymorphisms have been described and some have been implicated in common chronic inflammatory conditions including Crohn's disease and rheumatoid arthritis. In particular, two common polymorphisms affecting 15-20% of general population have been shown to result in gain-of-function phenotype associated with moderately increased IL-1? levels. Based on these preliminary data we propose the CENTRAL HYPOTHESIS that 1) NLRP3 is required for the progression of ethanol-induced fatty liver to ASH and fibrosis in mice; 2) Genetic variation in NLRP3-inflammasome expression predicts progression and/or severity of ALD and response to IL-1-based therapy in ASH. To investigate this hypothesis our proposal has following SPECIFIC AIMS. First: Determine the role of NLRP3 inflammasome activation on ALD progression from fatty liver to steatohepatitis and fibrosis. Second: Determine the role of genetic variations of NLRP3 inflammasome resulting in gain-of-function phenotypes in susceptibility to ALD and response to IL-1-based therapy in patients with ALD. To address these central issues, we have put together a Multi-PI investigative team including a Pioneered Scientist in Inflammasome Biology, and Experts in Cell Death, Fibrosis and Alcoholic Liver Disease Pathology. The results of these studies will uncover crucial aspects of NLRP3 inflammasome biology and its contribution to liver pathology in ALD that may lead to novel diagnostic and therapeutic strategies for patients with this disease.
/ RELEVANCE Growing evidence supports the a key role for NLRP3 inflammasomes, multi-protein cytoplasmic complex that serve as pattern recognition receptors, in various forms of liver diseases including alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) two of the most common liver disorders in the US for which no effective therapy is available. The results of proposed studies will uncover crucial aspects of NLRP3 Inflammasome biology and its contribution to liver pathology that may lead to novel therapeutic strategies.
