Uncovering liver macrophage subsets and the role of macrophage prolyl hydroxylases in the pathogenesis of non-alcoholic steatohepatitis and associated liver cancer 

Non-alcoholic fatty liver disease is an important cause of chronic liver disease in Western countries. The disease ranges from simple steatosis (lipid accumulation) to non-alcoholic steatohepatitis (NASH) (liver inflammation related to steatosis) which can result in liver cirrhosis and even in NASH-induced hepatocellular carcinoma (NASH-HCC). Macrophages (Mf) are innate immune cells with diverse functions related to their origin and local microenvironment. The liver harbors unique resident Mf, Kupffer cells (KCs), which provide first defense and are assisted by infiltrating Mf (iMf) in case of hepatic threat. Both KCs and iMf have been reported to play a role in the onset and progression of NASH(-HCC), however, the markers that have been used to denote these distinct Mf populations are not specific. Therefore, our first aim is to characterize the different Mf subsets and correlate this to disease progression by using KC specific markers, NASH(- HCC) mouse models and human samples. In addition, the phenotype/function of Mf is plastic and can be modulated as therapeutic strategy, shown in different experimental models. In this context, we are interested in prolyl hydroxylases (PHDs), cellular oxygen sensors that influence Mf function. Our second aim is to unravel the role of PHDs and the therapeutic potential of modulating PHD expression in KCs and iMf in NASH and NASH-HCC. We will therefore use mice with KCs and iMf selective PHD deletion and overexpression.