TRPM2 links oxidative stress to the NLRP3 inflammasome activation (P1268)

Exposure to particulate crystals, either environmental irritants or endogenous metabolites, can induce oxidative stress in phagocytes, which in turn triggers NLRP3–inflammasome mediated interleukin 1β (IL–1β) secretion to initiate undesired inflammatory responses associated with many autoinflammatory and metabolic diseases. Although mitochondrial reactive oxygen species (ROS), accumulated under oxidative stress, has been shown essential for NLRP3 inflammasome activation, little is known how ROS signals the assembly of the NLRP3 inflammasome. Here, we first identified liposomes as a novel group of particulate activators for NLRP3 inflammasome, and further demonstrated that this immune recognition process also requires mitochondrial ROS. Moreover, we found that stimulation of particulate substances (liposomes and crystals) induced a ROS–dependent calcium influx via the TRPM2 ion channel that directs the assembly of NLRP3 inflammasome. Macrophages deficient in TRPM2 displayed drastically impaired NLRP3 inflammasome activation and IL–1β secretion in response to liposomes/crystals. Consistently, Trpm2−/− mice were resistant to crystals/liposomes–induced, IL–1β–mediated peritonitis in vivo. Taken together, these results identify TRPM2 as a novel player that links particulates–induced oxidative stress to the NLRP3 inflammasome activation. Thus, targeting TRPM2 may be beneficial for inflammatory disorders associated with deranged NLRP3 inflammasome activation.