TRPM2 links oxidative stress to NLRP3 inflammasome activation

Zhenyu Zhong, Yougang Zhai, Shuang Liang, Yasuo Mori, Renzhi Han, Fayyaz S. Sutterwala and Liang Qiao ()
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Zhenyu Zhong: Stritch School of Medicine, Loyola University Chicago
Yougang Zhai: Stritch School of Medicine, Loyola University Chicago
Shuang Liang: Graduate Program of Molecular Biology, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago
Yasuo Mori: Laboratory of Molecular Biology, Graduate School of Engineering, Kyoto University
Renzhi Han: Stritch School of Medicine, Loyola University Chicago
Fayyaz S. Sutterwala: Inflammation Program, Carver College of Medicine, University of Iowa
Liang Qiao: Stritch School of Medicine, Loyola University Chicago

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2608

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