TRPM2 links oxidative stress to NLRP3 inflammasome activation

• Published in: Nature communications 2013-03, Vol.4 (1), p.1611-1611
• Main Authors: Zhong, Zhenyu, Zhai, Yougang, Liang, Shuang, Mori, Yasuo, Han, Renzhi, Sutterwala, Fayyaz S., Qiao, Liang
• Format: Article
• Language: English
• Subjects: 631/250/256/2177; 631/250/516; Animals; Carrier Proteins - physiology; Cell Line; Enzyme-Linked Immunosorbent Assay; Humanities and Social Sciences; Humans; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Liposomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Science; Science (multidisciplinary); Spectrometry, Fluorescence; TRPM Cation Channels - genetics; TRPM Cation Channels - physiology
• ISSN: 2041-1723
• DOI: 10.1038/ncomms2608

Exposure to particulate crystals can induce oxidative stress in phagocytes, which triggers NLRP3 inflammasome-mediated interleukin-1β secretion to initiate undesirable inflammatory responses that are associated with both autoinflammatory and metabolic diseases. Although mitochondrial reactive oxygen species have a central role in NLRP3 inflammasome activation, how reactive oxygen species signal assembly of the NLRP3 inflammasome remains elusive. Here, we identify liposomes as novel activators of the NLRP3 inflammasome and further demonstrate that liposome-induced inflammasome activation also requires mitochondrial reactive oxygen species. Moreover, we find that stimulation with liposomes/crystals induced reactive oxygen species-dependent calcium influx via the TRPM2 channel and that macrophages deficient in TRPM2 display drastically impaired NLRP3 inflammasome activation and interleukin-1β secretion. Consistently, Trpm2 −/− mice are resistant to crystal-/liposome-induced interleukin-1β-mediated peritonitis in vivo . Together, these results identify TRPM2 as a key factor that links oxidative stress to the NLRP3 inflammasome activation. Therefore, targeting TRPM2 may be effective for the treatment of NLRP3 inflammasome-associated inflammatory disorders. Activation of the NLRP3 inflammasome by particulate matter such as crystals is known to depend on the generation of reactive oxygen species. Zhong et al . now show that liposomes stimulate the same pathway, and oxidative stress activates NLRP3 by promoting calcium influx through TRPM2 channels.