细胞外atp诱导的NLRP3炎性体激活需要线粒体功能

Daichi Sadatomi, Kazutaka Nakashioya, Sayaka Mamiya, Shino Honda, Yuka Kameyama, Y. Yamamura, S. Tanimura, K. Takeda
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引用次数: 41

摘要

NLRP3炎症小体在炎症细胞因子的加工和释放中起关键作用,如白细胞介素-1β (IL-1β)和IL-18。越来越多的证据表明,线粒体是多种炎症刺激诱导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。在这里,我们证明线粒体功能是细胞外atp诱导的NLRP3炎性体激活所必需的。细胞外ATP诱导原代小鼠巨噬细胞线粒体膜电位丧失和线粒体断裂的方式不同于其他刺激。CCCP是一种解偶联剂,抗霉素A是一种线粒体电子传递链抑制剂,可以抑制ATP诱导的IL-1β释放,而其他刺激则没有作用。CCCP不抑制atp诱导的活性氧的产生和细胞死亡,这两者都可以促进IL-1β的释放,但确实抑制了atp诱导的caspase-1的激活,caspase-1是NLRP3炎症小体的一个组成部分。这些结果表明,atp诱导的NLRP3炎性体激活在一定程度上需要线粒体功能。与许多先前的报道相反,功能失调的线粒体促进NLRP3炎性小体的激活,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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation
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.
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