Aggregatibacter actinomycetemcomitans cytolethal distending toxin activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines.
Aggregatibacter actinomycetemcomitans cytolethal distending toxin activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines.
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放线菌聚集菌致死膨胀毒素可激活人巨噬细胞中的 NLRP3 炎症小体，导致促炎细胞因子的释放。
DOI：
10.1128/iai.03132-14
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发表时间：
2015
影响因子：
3.1
通讯作者：
Boesze-Battaglia,Kathleen
中科院分区：
文献类型：
--
作者：
Shenker,BruceJ;Ojcius,DavidM;Walker,LisaP;Zekavat,Ali;Scuron,MonikaDamek;Boesze-Battaglia,Kathleen
细胞致死性膨胀毒素(CDT)是由一些能够引起感染和炎症性疾病的细菌产生的。我们以前对伴放线放线杆菌CDT的研究表明，活性毒素亚基不仅作为磷脂酰肌醇-3，4，5-三磷酸(PIP3)磷酸酶发挥功能，而且暴露在该毒素下的巨噬细胞可被刺激产生促炎细胞因子。我们现在证明，CDT诱导的促炎反应涉及NLRP3炎症体的激活。使用特异的抑制剂和短发夹状RNA(ShRNA)来证明NLRP3和ASC以及caspase-1的需求。此外，CDT介导的炎性小体激活依赖于上游信号，包括活性氧(ROS)的产生和CDT诱导的细胞外ATP水平的增加。细胞外ATP水平的升高有助于激活P2X7嘌呤能受体，导致K+外流。讨论了活性毒素亚基CDtB作为脂磷酸酶、激活NLRP3炎性小体和诱导促炎细胞因子反应能力之间的关系。这些研究为CDT在介导CDT产生菌(如伴生放线杆菌)引起的疾病发病机制中的毒力潜力提供了新的见解。
The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies with Actinobacillus actinomycetemcomitans Cdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive oxygen species (ROS) generation and Cdt-induced increases in extracellular ATP levels. Increases in extracellular ATP levels contribute to the activation of the P2X7purinergic receptor, leading to K+efflux. The relationship between the abilities of the active toxin subunit CdtB to function as a lipid phosphatase, activate the NLRP3 inflammasome, and induce a proinflammatory cytokine response is discussed. These studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as Aggregatibacter actinomycetemcomitans.
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