Innate Immunity in NASH

Nonalcoholic steatohepatitis (NASH), a cell death and inflammation-associated nonalcoholic fatty liver disease (NAFLD), is the leading cause of hepatocellular carcinoma (HCC) and end-stage liver failure worldwide. There is no effective therapeutic drug for NASH to date, highlighting an urgent need for the identification of novel targets for this devastating disease. Evidence cumulated over the past decade strongly suggest that the innate immune system, specifically the liver-resident macrophages (Kupffer cells) and recruited monocyte-derived macrophages, play a key role in NASH progression and pathogenesis. The current study aims to elucidate the mechanisms by which macrophage cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates liver fibrosis and NASH pathogenesis. We found that macrophage-specific knockout of cGAS or STING promotes liver inflammation, apoptosis, and fibrosis, suggesting this DNA sensing innate immune pathway protects, rather than promotes, NASH progression in mice. However, how cGAS or STING deficiency leads to NASH pathogenesis remains unknown. Our preliminary study suggests that macrophage cGAS may suppress NASH development by facilitating macrophage phagocytosis via both STING-dependent and independent novel mechanisms. To test this hypothesis, we will 1) delineate the STING-independent molecular mechanism by which cGAS promotes macrophages phagocytosis; 2) Elucidate the STING-dependent signaling mechanism by which cGAS regulates macrophage phagocytosis; and 3) Explore the physiological role of cGAS-regulated phagocytosis in preventing liver fibrosis and NASH. Our study will dissect a novel role mechanism by which cGAS regulates macrophage phagocytosis and prevents NASH. The comprehensive understanding of the fundamental functions of the innate immunity and macrophage biology will not only provide a proof-of-concept for rethinking the nature of this devastating liver disease, but also open a new therapeutic avenue for developing therapeutic treatment of NASH.