TRPM2 links oxidative stress to NLRP3 inflammasome activation.
TRPM2 links oxidative stress to NLRP3 inflammasome activation.
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DOI：
10.1038/ncomms2608
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发表时间：
2013
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
暴露在颗粒晶体中可诱导吞噬细胞的氧化应激，从而触发NLRP3炎症小体介导的白介素1β(IL-1β)分泌，启动与自身炎症和代谢性疾病相关的不良炎症反应。尽管线粒体活性氧物种(ROS)在NLRP3炎症体的激活中起着核心作用，但ROS如何信号NLRP3炎症体的组装仍然是个未知数。在这里，我们确定脂质体是NLRP3炎症体的新的激活剂，并进一步证明脂质体诱导的炎症体激活也需要线粒体ROS。此外，我们还发现，脂质体/晶体刺激可通过TRPM2通道诱导依赖ROS的钙内流，而缺乏TRPM2的巨噬细胞表现出显著抑制NLRP3炎性小体激活和IL-1β的分泌。在体内，TRPM2−/−小鼠对晶体/脂质体诱导的IL-1β介导的腹膜炎一直具有抵抗力。综上所述，这些结果确认TRPM2是将氧化应激与NLRP3炎症体激活联系起来的关键参与者。因此，靶向TRPM2治疗NLRP3炎症性疾病可能是有效的。
Exposure to particulate crystals can induce oxidative stress in phagocytes, which triggers NLRP3 inflammasome-mediated interleukin 1β (IL-1β) secretion to initiate undesirable inflammatory responses that are associated with both autoinflammatory and metabolic diseases. Although mitochondrial reactive oxygen species (ROS) play a central role in NLRP3 inflammasome activation, how ROS signal assembly of the NLRP3 inflammasome remains elusive. Here, we identify liposomes as novel activators of NLRP3 inflammasome and further demonstrate that liposome-induced inflammasome activation also requires mitochondrial ROS. Moreover, we found that stimulation with liposomes/crystals induced ROS-dependent calcium influx via the TRPM2 channel and that macrophages deficient in TRPM2 displayed drastically impaired NLRP3 inflammasome activation and IL-1β secretion. Consistently, Trpm2−/− mice were resistant to crystal-/liposome-induced IL-1β-mediated peritonitis in vivo. Together, these results identify TRPM2 as a key player that links oxidative stress to the NLRP3 inflammasome activation. Therefore, targeting TRPM2 may be effective for the treatment of NLRP3 inflamamsome-associated inflammatory disorders.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
4.4
作者：
Li, Hanfen;Willingham, Stephen B.;Ting, Jenny P. -Y.;Re, Fabio
通讯作者：
Re, Fabio
影响因子：
7.3
作者：
Fonfria, E;Marshall, ICB;McNulty, S
通讯作者：
McNulty, S
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20102049
发表时间：
2011-03-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bulua AC;Simon A;Maddipati R;Pelletier M;Park H;Kim KY;Sack MN;Kastner DL;Siegel RM
通讯作者：
Siegel RM