Bacterial Pathogenesis and Innate Immunity laboratory, Inserm U851 "Immunity, Infection and Vaccination," Claude Bernard Lyon I University, Lyon, France.
Glia. 2013 Apr;61(4):539-49. doi: 10.1002/glia.22454. Epub 2013 Jan 28.
Microglial cells constitute the first line of defense of the central nervous system (CNS) against microbial invasion. Pathogens are detected thanks to an array of innate immune receptors termed pattern recognition receptors (PRRs). PRRs have been thoroughly characterized in bone marrow-derived macrophages, but the PRRs repertoire and functionality in microglial cells remain largely unknown. Microglial cells express various Toll-like Receptors and the Nod1/2 receptors. Recently, a novel innate immune signalling pathway, the inflammasome pathway has been uncovered. Inflammasome activation leads to caspase-1 activation, release of the proinflammatory cytokines, IL-1β and IL-18 and cell death in a process termed pyroptosis. One inflammasome receptor, NLRP3, has been characterized in microglial cells and associated with response to infections and in the initiation of neuro-degeneration in an Alzheimer's disease model. Legionella pneumophila (L.pneumophila) is a flagellated bacterium replicating within macrophages. In bone marrow-derived macrophages, L. pneumophila is detected in a flagellin-dependent manner by the Naip5-NLRC4 (Ipaf) inflammasome pathway. In this study, we decided to use L. pneumophila to investigate the presence and the functionality of this inflammasome in primary murine microglial cells. We show that microglial cells detect L. pneumophila infection in a flagellin-dependent manner leading to caspase-1-mediated bacterial growth restriction, infected cell death and secretion of the proinflammatory cytokines IL-1β and IL18. Overall, our data demonstrate that microglial cells have a functional Naip5-NLRC4 inflammasome likely to be important to monitor and clear CNS infections by flagellated bacteria.
小胶质细胞构成了中枢神经系统 (CNS) 抵御微生物入侵的第一道防线。病原体通过一系列称为模式识别受体 (PRRs) 的固有免疫受体被检测到。PRRs 在骨髓来源的巨噬细胞中得到了彻底的研究，但小胶质细胞中的 PRR 谱和功能在很大程度上仍然未知。小胶质细胞表达各种 Toll 样受体和 Nod1/2 受体。最近，一种新的先天免疫信号通路，即炎症小体通路被发现。炎症小体的激活导致半胱天冬酶-1 的激活，前炎性细胞因子 IL-1β 和 IL-18 的释放以及细胞死亡，这一过程称为细胞焦亡。一种炎症小体受体 NLRP3 已在小胶质细胞中得到表征，并与感染反应和阿尔茨海默病模型中的神经变性起始有关。嗜肺军团菌 (L.pneumophila) 是一种在巨噬细胞内复制的鞭毛细菌。在骨髓来源的巨噬细胞中，L. pneumophila 通过 Naip5-NLRC4 (Ipaf) 炎症小体途径以依赖鞭毛蛋白的方式被检测到。在这项研究中，我们决定使用 L. pneumophila 来研究原发性小鼠小胶质细胞中这种炎症小体的存在和功能。我们表明，小胶质细胞以依赖鞭毛蛋白的方式检测到 L. pneumophila 感染，导致半胱天冬酶-1 介导的细菌生长限制、感染细胞死亡和前炎性细胞因子 IL-1β 和 IL18 的分泌。总的来说，我们的数据表明，小胶质细胞具有功能性的 Naip5-NLRC4 炎症小体，这可能对监测和清除鞭毛菌引起的中枢神经系统感染很重要。
