Role of macrophage NLRP3 inflammasome activation in real-ambient particulate matter-induced abnormal hepatic glucose metabolism.

Evidence regarding the effects of particulate matter (PM) exposure on hepatic glucose metabolism and insulin resistance is limited, and its mechanisms remain unclear. Macrophages, as key regulators of the liver microenvironment, may mediate PM-induced metabolic processes. This study used an individually ventilated cage (IVC)-based real-ambient PM exposure system mouse model, co-cultured macrophages and hepatocytes, and NOD-like receptor protein 3 (Nlrp3)-knockdown model to investigate the impact of macrophages on hepatic insulin resistance (IR) and glucose metabolism under PM exposure. Our findings revealed that glycogen storage was impaired, insulin signaling was suppressed, the mRNA expression of glucose metabolism-related genes was altered, and the number of macrophages increased in the mouse liver after 15 weeks of PM exposure. Additionally, PM exposed mice exhibited reduced glucose tolerance and insulin sensitivity. In the transwell co-culture model, macrophages exposed to PM for 72 h exhibited NLRP3 inflammasome activation and IL-1β release, which were associated with lysosomal damage and cathepsin B release, accompanied by inhibition of insulin signaling and abnormal expression of glucose metabolism-related genes in hepatocytes. In vitro inhibition of NLRP3 and in vivo knockdown of Nlrp3 significantly attenuated these effects of PM exposure. Additionally, IL-1β inhibition improved glucose metabolism abnormalities. These findings reflect specific effects on insulin signaling and glucose metabolism mediated by the NLRP3 inflammasome or IL-1β. These results suggest that PM exposure leading to macrophage NLRP3 inflammasome activation and IL-1β release is an important cause of abnormal hepatic glucose metabolism, providing new insights into the underlying mechanisms of PM-related hepatic glucose metabolism and IR.