Co-stimulatory interactions in the development of Non-Alcoholic Steatohepatitis and Liver Fibrosis

• Applicant: Dr. Antonios Chatzigeorgiou
• Subject Area: Gastroenterology ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396067872

Obesity is strongly associated with pathologies such as insulin resistance and non-alcoholic fatty liver disease (NAFLD). The low grade inflammatory state present in obesity is a major component of the progression of NAFLD to non-alcoholic steatohepatitis (NASH), a disorder characterised by exacerbated hepatocellular injury that can lead to fibrosis, cirrhosis or even neoplasia. Although the study of inflammatory mechanisms implicated in the promotion of hepatic lipid accumulation, liver damage and fibrosis is a major target of NASH research, very little is known about the cellular interactions amongst cells of the innate and adaptive immunity as well as between immune cells and parenchymal cells of the liver that lead to NASH development. Therefore, in the current proposal, the applicant aims to unravel the pathophysiological events that determine the interactions between parenchymal cells, innate immunity and adaptive immunity in the steatotic liver environment, by focusing on a major player of cell-to-cell communication processes, the CD40/CD40L system. Our in vivo and in vitro preliminary data suggest that the CD40/CD40L duo has a predominant role in the hepatic immune-parenchymal cell crosstalk and thereby in the regulation of hepatic steatosis and progression to NASH. To this end, we will utilize genetically modified mice, including mice with hepatocyte- and myeloid/macrophage cell-specific ablation of CD40, as well as mice with lymphocyte-specific deletion of CD40L that will be assessed for diet-induced development of NAFLD and NASH. In addition, we will thoroughly investigate the molecular events (intercellular or intracellular) that are responsible for the CD40/CD40L-dependent regulation of steatohepatitis. We expect that these findings will significantly improve our understanding of the inflammatory cell interplay in the liver during NASH development and may pave the way for novel therapeutic strategies to prevent obesity-related NAFLD and transition to NASH.

• DFG Programme: Research Grants