Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.

中文翻译：

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IRF8调节NLRC4炎性小体激活的Naips转录。

炎性体活化对于抵抗各种微生物感染的宿主防御至关重要。NLRC4炎性体的激活需要通过NLR家族凋亡抑制蛋白（NAIP）检测鞭毛蛋白或III型分泌系统（T3SS）成分；然而，该途径的调控方式尚不清楚。在这里，我们发现干扰素调节因子8（IRF8）对于在鼠伤寒沙门氏菌，泰国伯克霍尔德氏菌或铜绿假单胞菌感染的骨髓来源的巨噬细胞中NLRC4炎性小体的最佳激活是必需的，但对于规范性和非典型性的激活都是必需的规范NLRP3，AIM2和Pyrin炎性小体。IRF8控制Naips的转录，以检测鞭毛蛋白或T3SS蛋白来介导NLRC4炎性体激活。此外，我们发现，由于IRF8在依赖于炎症小体的细胞因子的产生和发烧中的作用，因此可在体内提供针对细菌感染的保护作用。总之，我们的发现表明IRF8是NAIP和NLRC4炎性小体活化的关键调节剂，可抵抗细菌感染。