Influence of NLRP3 activation in monocyte-derived macrophages on NASH

• Applicant: Dr. Christian Stöß
• Subject Area: General and Visceral Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497483096

The metabolic dysfunction-associated steatotic liver disease, abbreviated as MASLD (formerly non-alcoholic fatty liver disease, NAFLD), is currently emerging as the leading global chronic liver disease. Its spectrum spans from pure steatosis to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), characterized by chronic inflammation and hepatocyte injury. This can progress to liver fibrosis and cirrhosis, thereby increasing the risk of hepatocellular carcinoma development. Moreover, compromised liver function adversely affects tumor resectability, elevates the risk of postoperative liver failure, and diminishes organ quality for transplantable livers. In the pathogenesis of MASH, inflammatory and immune signaling pathways play a pivotal role, culminating in the activation of the inflammasome, particularly NLRP3, in hepatocytes, stellate cells, and immune cells. The overall objective of this study is to investigate the cell-specific effects of activated NLRP3 signaling pathways on the biological activity of stellate cells and the progression of MASH in a mouse model. We hypothesize that NLRP3 activation promotes excessive tissue inflammation, leading to HSC activation, hepatocyte injury, and liver fibrosis, ultimately favoring MASH pathogenesis. Various cell-specific NLRP3 knock-in and knock-out experimental models will be employed to test the working hypothesis. Consequently, a comprehensive and critical insight into the role of NLRP3 activity and associated signaling pathways and cytokines, particularly IL-18 and IL-1β, in different cell populations in vivo and in vitro will be attainable. Findings from the animal model will be validated using human samples. By elucidating the molecular mechanisms, the groundwork for clinical therapies within the framework of translational research projects can be established in the long term.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ariel E. Feldstein