Exploration of the NLRP3 inflammasome as a key player in chronic liver disease

• Applicant: Professor Dr. Alexander Wree
• Subject Area: Gastroenterology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290021240

Hepatic inflammation is a common trigger of liver disease, and is considered the main driver of hepatic tissue damage leading to fibrogenesis and hepatocellular carcinoma (HCC). In Western countries, most chronic liver diseases (CLD) are attributed to chronic hepatitis B and C infection, alcohol consumption, metabolic diseases, drug/toxin-induced liver injury and auto-immune causes, including immune-mediated biliary diseases. Therefore, CLD are a serious public health burden and are a major cause of worldwide mortality and morbidity. Inflammasomes, intracellular multi-protein complexes, are expressed in both parenchymal and non-parenchymal cells in the liver and severe as key regulators of inflammation and cell fate. The most studied inflammasome NLRP3 assembles a complex comprised of the adaptor protein apoptosis associated speck like protein (ASC) and the serine protease caspase-1. The Nlrp3 inflammasome responds to cellular danger signals by activating caspase-1, releasing IL-1beta and IL-18, as well as initiating a novel pathway triggering programmed cell death termed pyroptosis. In particular NLRP3 activation and IL-1 signalling have been implicated in the pathogenesis of many liver diseases including: ischemia-reperfusion injury, drug-mediated, pathogen-mediated, or endotoxin-mediated pathology, as well as NAFLD and liver fibrosis. A role for NLRP3 inflammasome gain-of-function mutations was initially described in a group of rare autoinflammatory monogenic conditions, termed cryopyrin-associated periodic syndromes (CAPS). Subsequently, multiple gene polymorphisms in the NLRP3-inflammasome have been described and some have been implicated in common chronic inflammatory conditions including Crohns disease and rheumatoid arthritis. In particular, two common polymorphisms affecting 15-20% of general population, Q705K in NLRP3 and C10X in CARD8 have been shown to result in gain-of-function phenotype associated with disease severity and increased IL-1beta levels. We and others have recently demonstrated that NLRP3 activation is important in hepatic inflammation and fibrosis in experimental and human liver disease. Based on these data we propose the CENTRAL HYPOTHESIS that cell- and time-specific NLRP3 inflammasome activation is a central mechanism that triggers hepatic inflammation, programmed cell death, and liver fibrogenesis and finally liver cirrhosis. The key questions generated are separated in three aims as follows: Determine the role of NLRP3 inflammasome driven chronic inflammation on fibrogenesis and liver fibrosis. Determine the role of NLRP3 initiated caspase-1 activation, cytokine production and pyroptotic cell death on the development of inflammasome driven chronic inflammation, fibrogenesis and liver fibrosis. Determine the role of genetic variations that result in NLRP3 inflammasome gain-of-function phenotypes and how they affect susceptibility to chronic liver disease.

• DFG Programme: Research Grants