Understanding and modulating hepatic macrophage functionality in non-alcoholic fatty liver disease

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Liver macrophages are considered key in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophages can sense metabolic injury to hepatocytes, orchestrate inflammatory responses and promote fibrogenesis, but are also essential during tissue repair and regeneration. Hepatic macrophages comprise ontogenetically and functionally different subsets, including tissue-resident Kupffer cells and infiltrating monocyte-derived macrophages. State-of-the-art technologies, particularly single-cell RNA sequencing, multiplex immunostaining and spatial transcriptomics will be leveraged to characterize the functional diversity of macrophages including cell-cell interactions and identify targetable ligand-receptor pairs in human NAFLD patients. Subsequent functional studies via genetic and pharmacologic inhibition (or activation) in NAFLD mouse models and co-cultures (‘liver-on-a-chip’) will determine the role of specific macrophage subsets. We anticipate that human-based systematic analyses of macrophage heterogeneity and their interactions with neighboring cells, in conjunction with functional mouse studies, will not only provide unprecedented insights into the central but functionally diverse roles of macrophages in NAFLD, but create a pipeline of novel targets for therapeutic interventions to halt NAFLD progression or stimulate its regression. To achieve this, we seek to: 1. Define macrophage subsets via their phenotypic and spatial profile in NAFLD progression and resolution (based on human liver). 2. Identify the functional consequences of macrophage subset phenotypes on hepatic dysmetabolism, inflammation and fibrosis. 3. Characterize the prospects of rationally designed and personalized treatment approaches for modulating macrophage functionality in NAFLD. Our findings will provide a comprehensive picture of how hepatic macrophage subsets contribute to altered metabolism, inflammation and fibrosis in NAFLD and opportunities for novel therapeutic strategies.