Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11282-7. doi: 10.1073/pnas.1117765109. Epub 2012 Jun 25.
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca(2+) mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca(2+) mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca(2+) signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca(2+) release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca(2+)-mediated mitochondrial damage.
NLRP3（核苷酸结合域，富含亮氨酸重复序列家族，吡咯烷域包含 3）炎性小体介导炎症介质的产生，如 IL-1β 和 IL-18，因此涉及多种炎症过程，包括感染、败血症、自身炎症性疾病和代谢性疾病。NLRP3 炎性小体激活的近端步骤尚不清楚。在这里，我们阐明了钙动员在多种刺激物激活 NLRP3 炎性小体中的关键作用。我们证明，阻断钙动员会抑制 NLRP3 炎性小体复合物的组装和激活，并且在 ATP 刺激期间，钙信号在促进线粒体损伤中至关重要。C/EPB 同源蛋白是一种可以调节内质网钙释放的转录因子，它可以放大 NLRP3 炎性小体的激活，从而将内质网应激与 NLRP3 炎性小体的激活联系起来。我们的发现支持了钙介导的线粒体损伤激活 NLRP3 炎性小体的模型。
