Unravelling the heterogeneity and functions of hepatic myeloid cells in non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) results from accumulation of excessive fat in the liver. It encompasses simple steatosis (fatty liver) progressing through non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. It is the most common cause of chronic liver disease in western countries and is predicted to be the main cause of liver transplantation by 2030. As such NAFLD represents a significant clinical burden for which to date, there is no effective treatment. Multiple ‘hits’ are thought to contribute to the progression from steatosis to NASH. One of these ‘hits’ is activation of the immune system and the ensuing inflammatory response. Hepatic myeloid cells, including mononuclear phagocytes (MNPs) are thought to play an essential role in this, sensing excess lipids and other danger signals and initiating immune responses. However, MNPs represent a highly heterogeneous population, including multiple subtypes of dendritic cells and macrophages. To date these have been studied as a group rather than as individual cell types, leading to them being ascribed multiple and often contradictory roles depending on the experimental set up. Thus their specific contributions to NAFLD still remain unclear. I hypothesize that by dissecting the phenotypic and functional heterogeneity of hepatic MNPs, we will be able to unravel their roles in NAFLD and in the progression to NASH. Single cell technologies such as single cell RNA sequencing have revolutionised our ability to understand cellular heterogeneity. In addition, they have facilitated the development of novel genetic tools to study functions of specific cell types in vivo. I aim to use this technology and more specific in vivo tools to understand MNP phenotypic and functional heterogeneity in NAFLD in mice and men. This is essential for the development of novel therapeutic strategies targeting myeloid cells in what is becoming one of the biggest health challenges in the western world.