YCI Laboratory for Cellular Bioenergetic Network, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan.
Commun Biol. 2019 Jan 3;2:2. doi: 10.1038/s42003-018-0244-y. eCollection 2019.
The NLRP3 inflammasome is unique among pattern recognition receptors in using changes in cellular physiology as a mechanism for sensing host danger. To dissect the physiological network controlling inflammasome activation, we screened for small-molecule activators and suppressors of IL-1β release in macrophages. Here we identified niclosamide, a mitochondrial uncoupler, as an activator of NLRP3 inflammasome. We find that niclosamide inhibits mitochondria and induces intracellular acidification, both of which are necessary for inflammasome activation. Intracellular acidification, by inhibiting glycolysis, works together with mitochondrial inhibition to induce intracellular ATP loss, which compromises intracellular potassium maintenance, a key event to NLRP3 inflammasome activation. A modest decline in intracellular ATP or pH within an optimal range induces maximum IL-1β release while their excessive decline suppresses IL-1β release. Our work illustrates how energy metabolism converges upon intracellular potassium to activate NLRP3 inflammasome and highlights a biphasic relationship between cellular physiology and IL-1β release.
NLRP3 炎性小体作为一种模式识别受体，其独特之处在于它利用细胞生理学的变化作为感知宿主危险的机制。为了剖析控制炎性小体激活的生理网络，我们在巨噬细胞中筛选了白细胞介素-1β（IL-1β）释放的小分子激活剂和抑制剂。在这里，我们发现了尼氯柳胺，一种线粒体解偶联剂，可作为 NLRP3 炎性小体的激活剂。我们发现尼氯柳胺抑制线粒体并诱导细胞内酸化，这两者对于炎性小体的激活都是必需的。通过抑制糖酵解，细胞内酸化与线粒体抑制协同作用，导致细胞内三磷酸腺苷（ATP）损失，从而损害细胞内钾离子的维持，这是 NLRP3 炎性小体激活的关键事件。在最佳范围内，细胞内 ATP 或 pH 值的适度下降会诱导最大的 IL-1β 释放，而其过度下降会抑制 IL-1β 释放。我们的工作说明了能量代谢如何汇聚到细胞内钾离子以激活 NLRP3 炎性小体，并强调了细胞生理学和 IL-1β 释放之间的双相关系。
