Sadatomi Daichi, Nakashioya Kazutaka, Mamiya Sayaka, Honda Shino, Kameyama Yuka, Yamamura Yasuo, Tanimura Susumu, Takeda Kohsuke
Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
J Biochem. 2017 Jun 1;161(6):503-512. doi: 10.1093/jb/mvw098.
The NLRP3 inflammasome plays a critical role in the processing and release of inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. Accumulating evidence suggests that mitochondria are common mediators of NLRP3 inflammasome activation induced by a wide range of inflammatory stimuli; however, the precise role of mitochondria is still not fully understood. Here, we show that mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation. Extracellular ATP induced the loss of mitochondrial membrane potential and mitochondrial fragmentation in a different manner than other stimuli in primary mouse macrophages. CCCP, an uncoupler and antimycin A, an inhibitor of the mitochondrial electron transport chain, inhibited IL-1β release induced by ATP but not by other stimuli. CCCP did not inhibit the ATP-induced generation of reactive oxygen species and cell death, both of which are known to promote IL-1β release, but did inhibit the ATP-induced activation of caspase-1, a component of the NLRP3 inflammasome. These results suggest that mitochondrial function is required somewhat specifically for ATP-induced NLRP3 inflammasome activation. In contrast to many previous reports that dysfunctional mitochondria promote NLRP3 inflammasome activation, the function of intact mitochondria appears to be required for NLRP3 inflammasome activation, depending on the stimulus.
NLRP3炎性小体在炎性细胞因子如白细胞介素-1β（IL-1β）和IL-18的加工和释放中起关键作用。越来越多的证据表明，线粒体是多种炎性刺激诱导NLRP3炎性小体激活的常见介质；然而，线粒体的确切作用仍未完全了解。在此，我们表明线粒体功能是细胞外ATP诱导NLRP3炎性小体激活所必需的。细胞外ATP以与原代小鼠巨噬细胞中其他刺激不同的方式诱导线粒体膜电位丧失和线粒体碎片化。线粒体解偶联剂CCCP和线粒体电子传递链抑制剂抗霉素A抑制ATP诱导的IL-1β释放，但不抑制其他刺激诱导的IL-1β释放。CCCP不抑制ATP诱导的活性氧生成和细胞死亡，这两者均已知可促进IL-1β释放，但确实抑制ATP诱导的NLRP3炎性小体组分caspase-1的激活。这些结果表明，线粒体功能在一定程度上是ATP诱导NLRP3炎性小体激活所特有的。与许多先前关于功能失调的线粒体促进NLRP3炎性小体激活的报道相反，完整线粒体的功能似乎是NLRP3炎性小体激活所必需的，这取决于刺激因素。
