Metabo3DC · Understanding Metabolic Activation of Dendritic Cells in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a major global health problem with no approved treatments, and dire outcomes for patients. The pathogenesis of NAFLD is clearly linked to metabolic alterations, and is primarily characterized by excessive hepatic triglyceride content. Over time, metabolic dysfunction induces hepatic inflammation through mechanisms that remain poorly understood. This advanced disease stage, called non-alcoholic steatohepatitis (NASH), significantly raises the risk of hepatocellular carcinoma, cardiovascular disease and type-2 diabetes. My recent work has helped demonstrate that: 1) changes in conventional dendritic cell (cDC) populations in liver are closely associated with the development and the resolution of NASH in humans, and 2) extracellular metabolites can modulate cDC cytokine production and responses by rewiring their intracellular metabolic programs. Together, these studies indicate that alterations of the local hepatic metabolite environment could affect cDC function and thereby drive NASH pathogenesis.cDCs coordinate innate and adaptative immunity through cytokine secretion and antigen presentation. However, their role in NAFLD pathophysiology not well defined. In this ambitious multidisciplinary project, my objective is to systematically dissect the immuno-metabolic programs and functions of hepatic cDC during NASH progression and regression. First, we will identify disease-associated cDC subpopulations and their intracellular metabolic programs. We will then determine whether these cDC subtypes associate with specific local metabolic microenvironments in the liver in relation to histological features of NAFLD. Finally, we will determine how metabolic manipulation of cDC affects their immune function in the context of NASH. The present proposal has the potential to radically transform our understanding of NASH pathophysiology by delineating the specific links between metabolic dysfunction and innate immunity in liver disease.