Division of Pediatrics Infectious Disease and Immunology, Cedars-Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, CA 90048, USA.
Immunity. 2012 Mar 23;36(3):401-14. doi: 10.1016/j.immuni.2012.01.009. Epub 2012 Feb 16.
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 antiapoptotic 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.
我们报告称，在信号 1（NF-κB）存在的情况下，NLRP3 炎性体被线粒体凋亡信号激活，从而许可白细胞介素-1β（IL-1β）的产生。NLRP3 二级信号激活剂，如 ATP，诱导线粒体功能障碍和细胞凋亡，导致氧化的线粒体 DNA（mtDNA）释放到细胞质中，在细胞质中与 NLRP3 炎性体结合并激活它。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 炎性体激活，因为缺乏 mtDNA 的巨噬细胞产生的 IL-1β 显著减少，但仍发生细胞凋亡。氧化 mtDNA 与 NLRP3 炎性体的结合以及 IL-1β 的分泌都可以被氧化核苷 8-OH-dG 竞争性抑制。因此，我们的数据表明，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。这些结果通过将细胞质中氧化的 mtDNA 与 NLRP3 炎性体结合，提供了凋亡和炎性体激活之间缺失的一环。
