(540d) NLRP3 Inflammasome Activation Induced By Long Aspect Ratio Engineered Nanomaterials: Role of Oxidative Stress

NLRP3 inflammasome is an intracellular multi-protein complex assembled and activated upon exogenous stimuli including engineering nanomaterials (ENMs). Its activation has been increasingly implicated in nanomaterial-induced toxicity. However, the detailed mechanisms of inflammasome activation induced by ENMs are still not well understood. In this study, we examined the interaction mechanisms of ENMs with NLRP3 inflammasome using a library of long aspect ratio ENMs. We identified that besides the lysosomal damage and cathepsin B release, ROS generated through NADPH oxidase was found to play an important role in long aspect ratio ENM-induced NLRP3 inflammasome activation. The ROS generation could further lead to secondary cytosolic as well as mitochondrial ROS. In the meanwhile, we demonstrated that suppression of oxidative stress could attenuate inflammasome activation in vitro and the development of lung fibrosis upon ENM exposure in vivo. This study delineates mechanisms of NLRP3 inflammasome activation induced by long aspect ratio ENMs and identifies the role of oxidative stress in ENM-induced chronic lung inflammation and fibrosis.