Intracellular sensing of stress and danger signals initiates inflammatory innate immune responses by triggering inflammasome assembly, caspase-1 activation and pyroptotic cell death as well as the release of interleukin 1β (IL-1β), IL-18 and danger signals. NLRP3 broadly senses infectious patterns and sterile danger signals, resulting in the tightly coordinated and regulated assembly of the NLRP3 inflammasome, but the precise mechanisms are incompletely understood. Here, we identified NLRP11 as an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacted with NLRP3 and ASC, and deletion of NLRP11 specifically prevented NLRP3 inflammasome activation by preventing inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis and cytokine release but did not affect other inflammasomes. Restored expression of NLRP11, but not NLRP11 lacking the PYRIN domain (PYD), restored inflammasome activation. NLRP11 was also necessary for inflammasome responses driven by NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS). Because NLRP11 is not expressed in mice, our observations emphasize the specific complexity of inflammasome regulation in humans.

细胞内对压力和危险信号的感知通过触发炎性小体组装、caspase-1 激活和细胞焦亡以及白细胞介素 1β (IL-1β)、IL-18 和危险信号的释放来启动炎症性先天免疫反应。NLRP3 广泛感知感染模式和无菌危险信号，导致 NLRP3 炎性体的紧密协调和调节组装，但其确切机制尚不完全清楚。在这里，我们将 NLRP11 鉴定为人类巨噬细胞中 NLRP3 炎性体的重要组成部分。NLRP11 与 NLRP3 和 ASC 相互作用，NLRP11 的缺失通过阻止炎性体组装、NLRP3 和 ASC 聚合、caspase-1 激活、焦亡和细胞因子释放来特异性地阻止 NLRP3 炎性体激活，但不影响其他炎性体。恢复 NLRP11 的表达，而不是缺少 PYRIN 结构域 (PYD) 的 NLRP11，恢复炎性体激活。NLRP11 也是由 NLRP3 突变驱动的炎性体反应所必需的，该突变会导致隐热蛋白相关周期性综合征 (CAPS)。因为 NLRP11 不在小鼠中表达，我们的观察强调了人类炎症小体调节的特殊复杂性。