Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation
Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation
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DOI：
10.1002/eji.200737532
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Nunez, Gabriel
中科院分区：
文献类型：
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作者：
Franchi, Luigi;Stoolman, Joshua;Nunez, Gabriel
铜绿假单胞菌是一种机会性革兰氏阴性人类病原体，它在具有各种易感条件的个体中引发多种感染。感染后，铜绿假单胞菌在宿主体内诱导显著的炎症反应。然而，细菌识别和免疫反应诱导所涉及的机制了解甚少。在此我们报道，在铜绿假单胞菌肺部感染的体内模型中，Nod样受体家族成员Ipaf是实现最佳细菌清除所必需的。进一步分析表明，细菌鞭毛蛋白对caspase - 1和白细胞介素 - 1β至关重要，且这种活性依赖于Ipaf和衔接蛋白ASC，但不依赖于TLR5。值得注意的是，铜绿假单胞菌诱导巨噬细胞死亡，这一事件依赖于鞭毛蛋白和Ipaf，但不依赖于ASC。对铜绿假单胞菌突变体的分析显示，鞭毛蛋白的不同氨基酸残基对Ipaf和TLR5的感应至关重要。最后，铜绿假单胞菌激活caspase - 1和白细胞介素 - 1β分泌需要一个有功能的III型分泌系统，但不需要效应分子ExoS、ExoT和ExoY。这些结果为铜绿假单胞菌与宿主巨噬细胞的相互作用提供了新的见解，并表明鞭毛蛋白的不同区域可被Ipaf和TLR5感知。
Pseudomonas aeruginosa is an opportunistic Gram-negative human pathogen that is responsible for a broad range of infections in individuals with a variety of predisposing conditions. After infection, P. aeruginosa induces a marked inflammatory response in the host. However the mechanisms involved in bacterium recognition and induction of immune responses are poorly understood. Here we report that the Nod-like receptor family member Ipaf is required for optimal bacterial clearance in an in vivo model of P. aeruginosa lung infection. Further analysis showed that bacterial flagellin was essential for caspase-1 and IL-1 beta and this activity depended on Ipaf and the adaptor ASC but not TLR5. Notably, P. aeruginosa induced macrophage cell death and this event relied on flagellin and Ipaf but not on ASC. Analysis of Pseudomonas mutants revealed that different amino acid residues of flagellin were critical for sensing by Ipaf and TLR5. Finally, activation of caspase-1 and IL-1 beta secretion by P. aeruginosa required a functional type III secretion system, but not the effector molecules ExoS, ExoT and ExoY. These results provide new insight into the interaction of P. aeruginosa with host macrophages and suggest that distinct regions of flagellin are sensed by Ipaf and TLR5.