Pulmonary Inflammation Triggered by Ricin Toxin Requires Macrophages and IL-1 Signaling
Pulmonary Inflammation Triggered by Ricin Toxin Requires Macrophages and IL-1 Signaling
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DOI：
10.4049/jimmunol.0901119
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发表时间：
2009-07-15
影响因子：
4.4
通讯作者：
Magun, Bruce E.
中科院分区：
文献类型：
--
作者：
Lindauer, Meghan L.;Wong, John;Magun, Bruce E.
蓖麻毒素是一种强效的核糖毒素，由于其广泛的可获得性和向人群提供气雾剂的可能性，被认为是一种潜在危险的生物恐怖剂。对啮齿动物和非人类灵长类动物的研究表明，蓖麻毒素进入肺部系统会导致急性肺损伤和类似急性呼吸窘迫综合征的症状。越来越多的证据表明，蓖麻毒素引发的炎症反应是其致命性的原因。我们以前证明，蓖麻毒素给药到小鼠的肺导致肺巨噬细胞的死亡和促炎细胞因子的释放，这表明巨噬细胞可能是蓖麻毒素的主要目标。在这里，我们研究了蓖麻毒素介导的肺部炎症的发展中的巨噬细胞的需求，采用转基因（MAFIA）小鼠，表达诱导型基因驱动的Fas介导的巨噬细胞凋亡的c-fms启动子注射后的合成二聚体，AP 20187。给巨噬细胞耗竭的小鼠施用雾化蓖麻毒素导致炎症反应减少，包括中性粒细胞的募集、促炎转录物的表达和微血管通透性。当与用蓖麻毒素处理的对照小鼠相比时，用蓖麻毒素处理的巨噬细胞耗竭小鼠显示肺IL-1 β减少。使用缺乏IL-1的小鼠，我们发现蓖麻毒素诱导的炎症反应受到抑制，包括嗜中性粒细胞。对IL-1 α/β（-/-）小鼠联合给予蓖麻毒素和外源性IL-1 β可恢复嗜中性粒细胞。此外，IL 1 Ra/阿那白滞素联合治疗抑制蓖麻毒素介导的炎症反应，包括中性粒细胞的募集，促炎基因的表达和组织病理学。这些数据表明，蓖麻毒素引发的炎症过程中的巨噬细胞和IL-1信号的核心作用。免疫学杂志，2009，183：1419-1426.
Ricin is a potent ribotoxin considered to be a potentially dangerous bioterrorist agent due to its wide availability and the possibility of aerosol delivery to human populations. Studies in rodents and nonhuman primates have demonstrated that ricin delivered to the pulmonary system leads to acute lung injury and symptoms resembling acute respiratory distress syndrome. Increasing evidence suggests that the inflammatory effects triggered by ricin are responsible for its lethality. We demonstrated previously that ricin administered to the lungs of mice causes death of pulmonary macrophages and the release of proinflammatory cytokines, suggesting macrophages may be a primary target of ricin. Here we examined the requirement for macrophages in the development of ricin-mediated pulmonary inflammation by employing transgenic (MAFIA) mice that express an inducible gene driven by the c-fms promoter for Fas-mediated apoptosis of macrophages upon injection of a synthetic dimerizer, AP20187. Administration of aerosolized ricin to macrophage-depleted mice led to reduced inflammatory responses, including recruitment of neutrophils, expression of proinflammatory transcripts, and microvascular permeability. When compared with control mice treated with ricin, macrophage-depleted mice treated with ricin displayed a reduction in pulmonary IL-1 beta. Employing mice deficient in IL-1, we found that ricin-induced inflammatory responses were suppressed, including neutrophilia. Neutrophilia could be restored by co-administering ricin and exogenous IL-1 beta to IL-1 alpha/beta(-/-) mice. Furthermore, IL1Ra/anakinra cotreatment inhibited ricin-mediated inflammatory responses, including recruitment of neutrophils, expression of proinflammatory genes, and histopathology. These data suggest a central role for macrophages and IL-1 signaling in the inflammatory process triggered by ricin. The Journal of Immunology, 2009, 183: 1419-1426.