Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Cell. 2018 May 3;173(4):920-933.e13. doi: 10.1016/j.cell.2018.02.055. Epub 2018 Mar 22.
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.
炎性小体的激活对于宿主抵御各种微生物感染至关重要。NLRC4 炎性小体的激活需要 NLR 家族凋亡抑制蛋白（NAIPs）检测鞭毛蛋白或 III 型分泌系统（T3SS）成分；然而，该途径如何被调节尚不清楚。在这里，我们发现干扰素调节因子 8（IRF8）是骨髓来源的巨噬细胞感染沙门氏菌 Typhimurium、布氏杆菌泰国亚种或铜绿假单胞菌时 NLRC4 炎性小体最佳激活所必需的，但对于经典和非经典 NLRP3、AIM2 和 Pyrin 炎性小体的激活是可有可无的。IRF8 调控 Naip 的转录，以允许检测鞭毛蛋白或 T3SS 蛋白来介导 NLRC4 炎性小体的激活。此外，我们发现 IRF8 通过其在炎性小体依赖性细胞因子产生和细胞焦亡中的作用，赋予了对细菌感染的体内保护。总之，我们的研究结果表明，IRF8 是 NAIPs 和 NLRC4 炎性小体激活的关键调节剂，可用于防御细菌感染。
