Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia
Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia
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DOI：
10.1172/jci66142
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发表时间：
2013-04-01
影响因子：
15.9
通讯作者：
Prince, Alice S.
中科院分区：
文献类型：
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作者：
Cohen, Taylor S.;Prince, Alice S.
呼吸道对吸入细菌的感染有非常好的防御，多个促炎信号级联招募吞噬细胞清除气道病原体。然而，有效激活破坏性先天免疫反应的生物体，如由炎性小体和caspase-1介导的机体，可能导致肺部损伤并干扰细菌清除。胞外条件致病菌铜绿假单胞菌不仅表达与病原体相关的激活上皮细胞和免疫细胞nf - κ B信号的分子模式，还表达激活NLRC4炎性体的鞭毛。我们证明，在小鼠急性肺炎模型中，炎症小体信号的诱导，主要归因于肺泡巨噬细胞，损害了铜绿假单胞菌的清除，并与细胞凋亡/焦亡和死亡率增加有关。限制炎性小体激活的策略，包括fliC突变体感染、巨噬细胞的消耗、NLRC4的缺失、IL-1 β的减少和。在IL-1R或il - 18r缺失的小鼠中，IL-18的产生、caspase-1的抑制和下游信号的抑制都导致细菌清除率增强和病理减轻。这些结果表明，炎性小体提供了一个潜在的目标，以限制急性铜绿假单胞菌肺部感染的病理后果。
The respiratory tract is exceptionally well defended against infection from inhaled bacteria, with multiple proinflammatory signaling cascades recruiting phagocytes to clear airway pathogens. However, organisms that efficiently activate damaging innate immune responses, such as those mediated by the inflammasome and caspase-1, may cause pulmonary damage and interfere with bacterial clearance. The extracellular, opportunistic pathogen Pseudomonas aeruginosa expresses not only pathogen-associated molecular patterns that activate NF-kappa B signaling in epithelial and immune cells, but also flagella that activate the NLRC4 inflammasome. We demonstrate that induction of inflammasome signaling, ascribed primarily to the alveolar macrophage, impaired P. aeruginosa clearance and was associated with increased apoptosis/pyroptosis and mortality in a murine model of acute pneumonia. Strategies that limited inflammasome activation, including infection by fliC mutants, depletion of macrophages, deletion of NLRC4, reduction of IL-1 beta and. IL-18 production, inhibition of caspase-1, and inhibition of downstream signaling in IL-1R- or IL-18R-null mice, all resulted in enhanced bacterial clearance and diminished pathology. These results demonstrate that the inflammasome provides a potential target to limit the pathological consequences of acute P. aeruginosa pulmonary infection.