Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Int J Mol Sci. 2021 Jan 21;22(3):1048. doi: 10.3390/ijms22031048.
Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1-mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro-IL-1β and pro-IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.
天然免疫受体在检测到病原体相关分子模式（PAMPs）和损伤相关分子模式（DAMPs）后，会引发宿主免疫反应或炎症反应。在天然免疫受体中，核苷酸结合寡聚化结构域（NOD）样受体（NLRs）在检测细胞溶质 PAMPs 和 DAMPs 方面发挥着关键作用。一些 NLR 可以形成一种称为炎性体的多蛋白细胞溶质复合物。炎性体的激活触发半胱天冬酶-1 介导的孔形成蛋白 gasdermin D（GSDMD）的切割，这驱动了一种称为细胞焦亡的炎症细胞死亡形式。同时，激活的半胱天冬酶-1 将不成熟的细胞因子前白细胞介素-1β（pro-IL-1β）和前白细胞介素-18（pro-IL-18）切割成其活性形式，这些活性形式可以通过 GSDMD 膜孔释放。NLR 家族凋亡抑制蛋白（NAIP）-NLR 家族半胱氨酸天冬氨酸蛋白酶募集域蛋白 4（NLRC4）炎性体对于针对革兰氏阴性菌的免疫反应至关重要。NLRC4 通过 NAIPs 感知革兰氏阴性菌的 III 型分泌系统（T3SS）蛋白而被激活，例如沙门氏菌。NAIPs 和 NLRC4 的突变与人类自身炎症性疾病有关。在这篇综述中，我们强调了 NAIP/NLRC4 炎性体在宿主防御、自身炎症性疾病、癌症和细胞死亡中的作用。我们还讨论了指向 NLRC4 在 PANoptosis 中的作用的证据，PANoptosis 最近被确定为一种独特的炎症程序性细胞死亡途径，在多种疾病中具有重要的生理相关性。对 NLRC4 炎性体及其在 PANoptosis 中的潜在作用的深入了解为确定针对疾病的新治疗策略铺平了道路。
