Danger signals and pathways of macrophage activation in MASH
Inflammatory cell activation drives diverse cellular programming in steatohepatitis. Our studies revealed that activation of the multiprotein complex, inflammasome, contributes to metabolic dysfunction associated steatohepatitis (MASH) involving the NLRP3 and AIM2 inflammasomes both in hepatocytes and bone marrow-derived cells. Activation of liver immune cells is triggered by damage-associated molecular patterns (DAMPs) released from hepatocytes and increased circulating endotoxin levels amplify this response in MASH. In a high fat/cholesterol/sugar diet-induced metabolic syndrome and MASH in mice, accumulation of DAMPs paralleled the evolution of MASH from MAFLD suggesting the importance of DAMPs in disease progression. This suggested that activation of multiple pattern recognition signaling pathways occurs in both hepatocytes and immune cells in the liver and crosstalk between hepatocytes and immune cells amplifies inflammation and fibrosis in MASH. We identified that Hypoxia-inducible factor-1 (HIF-1α) upregulation in hepatocytes induces steatosis. Increased HIF-1α in hepatic macrophages and in MASH patients circulating monocytes is linked to impaired autophagy and this contributes to increased IL-1ß production in MASH. Our results suggest that macrophage activation in MASH involves multiple signals and a complex interplay between HIF-1α and autophagy as these pathways promote proinflammatory overactivation in MASH.
