Centre International de Recherche en Infectiologie, Université de Lyon, Lyon 69007, France;
J Immunol. 2013 Oct 1;191(7):3847-57. doi: 10.4049/jimmunol.1203326. Epub 2013 Aug 23.
The inflammasome is a signaling platform that is central to the innate immune responses to bacterial infections. Francisella tularensis is a bacterium replicating within the host cytosol. During F. tularensis subspecies novicida infection, AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1β and IL-18. Activation of this canonical inflammasome pathway is key to limit F. novicida infection. In this study, by comparing the immune responses of AIM2 knockout (KO), ASC(KO), and Casp1(KO) mice in response to F. novicida infection, we observed that IFN-γ levels in the serum of Casp1(KO) mice were much higher than the levels observed in AIM2(KO) and ASC(KO) mice. This difference in IFN-γ production was due to a large production of IFN-γ by NK cells in Casp1(KO) mice that was not observed in ASC(KO) mice. The deficit in IFN-γ production observed in ASC(KO) mice was not due to a reduced Dock2 expression or to an intrinsic defect of ASC(KO) NK cells. We demonstrate that in infected Casp1(KO) mice, IFN-γ production is due to an ASC-dependent caspase-1-independent pathway generating IL-18. Furthermore, we present in vitro data suggesting that the recently described AIM2/ASC/caspase-8 noncanonical pathway is responsible for the caspase-1-independent IL-18 releasing activity. To our knowledge, this study is the first in vivo evidence of an alternative pathway able to generate in a caspase-1-independent pathway bioactive IL-18 to boost the production of IFN-γ, a cytokine critical for the host antibacterial response.
炎症小体是一种信号平台，对于细菌感染的固有免疫反应至关重要。弗朗西斯菌是一种在宿主细胞质中复制的细菌。在弗氏志贺菌亚种 novicida 感染过程中，AIM2，一种感知细胞质 DNA 的炎症小体受体，以 ASC 依赖的方式激活 caspase-1，导致细胞焦亡和促炎细胞因子 IL-1β 和 IL-18 的释放。这种经典炎症小体途径的激活对于限制弗氏 novicida 感染至关重要。在这项研究中，通过比较 AIM2 敲除 (KO)、ASC(KO) 和 Casp1(KO) 小鼠对弗氏 novicida 感染的免疫反应，我们观察到 Casp1(KO) 小鼠血清中的 IFN-γ 水平远高于 AIM2(KO) 和 ASC(KO) 小鼠。IFN-γ 产生的这种差异是由于 Casp1(KO) 小鼠中 NK 细胞大量产生 IFN-γ所致，而 ASC(KO) 小鼠中未观察到这种情况。在 ASC(KO) 小鼠中观察到的 IFN-γ 产生不足不是由于 Dock2 表达减少或 ASC(KO) NK 细胞的内在缺陷所致。我们证明，在感染的 Casp1(KO) 小鼠中，IFN-γ 的产生是由于 ASC 依赖性 caspase-1 非依赖性途径产生 IL-18。此外，我们提供了体外数据表明，最近描述的 AIM2/ASC/caspase-8 非经典途径负责 caspase-1 非依赖性 IL-18 释放活性。据我们所知，这项研究首次在体内证明了一种替代途径，能够以 caspase-1 非依赖性途径产生生物活性的 IL-18，从而增强 IFN-γ 的产生，IFN-γ 是宿主抗细菌反应的关键细胞因子。
