Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
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DOI：
10.1016/j.immuni.2012.01.009
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发表时间：
2012-03-23
期刊：
影响因子：
32.4
通讯作者：
Arditi M
中科院分区：
文献类型：
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作者：
Shimada K;Crother TR;Karlin J;Dagvadorj J;Chiba N;Chen S;Ramanujan VK;Wolf AJ;Vergnes L;Ojcius DM;Rentsendorj A;Vargas M;Guerrero C;Wang Y;Fitzgerald KA;Underhill DM;Town T;Arditi M
我们报道，在信号1 （NF-κB）存在的情况下，NLRP3炎症小体被线粒体凋亡信号激活，从而导致白细胞介素-1β (IL-1β)的产生。NLRP3次级信号激活剂如ATP诱导线粒体功能障碍和凋亡，导致氧化的线粒体DNA （mtDNA）释放到细胞质中，并在细胞质中结合并激活NLRP3炎性体。抗凋亡蛋白Bcl-2反向调节线粒体功能障碍和NLRP3炎性体激活。线粒体DNA直接诱导NLRP3炎性体活化，因为缺乏线粒体DNA的巨噬细胞严重减弱了IL-1β的产生，但仍发生凋亡。氧化核苷8-OH-dG可竞争性地抑制氧化mtDNA与NLRP3炎性体的结合和IL-1β的分泌。因此，我们的数据显示，程序性细胞死亡过程中释放的氧化mtDNA导致NLRP3炎性体的激活。这些结果通过细胞质氧化mtDNA与NLRP3炎症小体的结合，提供了细胞凋亡和炎症小体活化之间缺失的联系。
We report that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1β (IL-1β). NLRP3 secondary signal activators such as ATP induced mitochondrial dysfunction and apoptosis, resulting in release of oxidized mitochondrial DNA (mtDNA) into the cytosol, where it bound to and activated the NLRP3 inflammasome. The anti-apoptotic protein Bcl-2 inversely regulated mitochondrial dysfunction and NLRP3 inflammasome activation. Mitochondrial DNA directly induced NLRP3 inflammasome activation, because macrophages lacking mtDNA had severely attenuated IL-1β production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1β secretion could be competitively inhibited by the oxidized nucleoside, 8-OH-dG. Thus, our data reveal that oxidized mtDNA released during programmed cell death causes activation of the NLRP3 inflammasome. These results provide a missing link between apoptosis and inflammasome activation, via binding of cytosolic oxidized mtDNA to the NLRP3 inflammasome.
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影响因子：
4
作者：
Akahoshi, T;Nagaoka, T;Kondo, H
通讯作者：
Kondo, H
DOI：
10.1073/pnas.0611496104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
通讯作者：
Ting, Jenny Pan-Yun
影响因子：
3.2
作者：
Kage, Hirokazu;Takaya, Akiko;Yamamoto, Tomoko
通讯作者：
Yamamoto, Tomoko
影响因子：
4.8
作者：
Esteve, JM;Mompo, J;Pallardó, FV
通讯作者：
Pallardó, FV
影响因子：
30.5
作者：
通讯作者：
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