Receptor-Interacting Protein 2 Controls Pulmonary Host Defense to Escherichia coli Infection via the Regulation of Interleukin-17A
Receptor-Interacting Protein 2 Controls Pulmonary Host Defense to Escherichia coli Infection via the Regulation of Interleukin-17A
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DOI：
10.1128/iai.05641-11
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发表时间：
2011-11-01
影响因子：
3.1
通讯作者：
Jeyaseelan, Samithamby
中科院分区：
文献类型：
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作者：
Balamayooran, Theivanthiran;Batra, Sanjay;Jeyaseelan, Samithamby
宿主受体对微生物模式的识别是导致嗜中性粒细胞依赖性宿主抗性的多步骤序列中的第一步。虽然膜结合传感器在细菌识别中的作用已经详细研究，但胞质传感器在肺中的重要性在很大程度上未被探索。在这种情况下，有一个主要的缺乏理解的下游信号介质，如细胞和/或分子，在急性细胞外革兰氏阴性细菌肺炎。为了确定NOD样受体（NLR）的作用，我们使用了一个实验性大肠杆菌感染模型，该模型使用了编码NLR接头受体相互作用蛋白2（RIP 2）的基因缺陷的小鼠。RIP 2（-/-）小鼠感染E.大肠杆菌感染显示较高的细菌负荷和减少的中性粒细胞募集和肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、巨噬细胞炎性蛋白2（MIP-2）和CXCL 5/LIX表达，沿着肺中减弱的组织病理学变化。在感染后的RIP 2（-/-）小鼠中观察到IL-17 A水平降低，沿着产生IL-17 A的T细胞数量减少。RIP 2（-/-）小鼠还显示肺中IL-6和IL-23水平降低，沿着感染后STAT 3活化降低。此外，感染RIP 2（-/-）小鼠肺中NF-κ B和丝裂原活化蛋白激酶（MAPK）的活化以及细胞间粘附分子1（ICAM-1）和血管细胞粘附分子1（VCAM-1）的表达在感染后减弱。尽管感染后RIP 2（-/-）小鼠中中性粒细胞向血液的动员受损，但在感染的野生型（WT）和RIP 2（-/-）小鼠之间，血液和肺中性粒细胞上的CD 62 P、CD 11 a/18、CD 11b和CXCR 2的表达没有改变。因此，RIP 2通过（i）IL-17 A调节和（ii）中性粒细胞向血液的动员，有助于嗜中性粒细胞依赖性宿主防御细胞外革兰氏阴性病原体。
Recognition of microbial patterns by host receptors is the first step in a multistep sequence leading to neutrophil-dependent host resistance. Although the role of membrane-bound sensors in bacterial recognition has been examined in detail, the importance of cytosolic sensors in the lungs is largely unexplored. In this context, there is a major lack of understanding related to the downstream signaling mediators, such as cells and/or molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to determine the role of NOD-like receptors (NLRs), we used an experimental Escherichia coli infection model using mice deficient in the gene coding for the NLR adaptor, receptor-interacting protein 2 (RIP2). RIP2(-/-) mice with E. coli infection displayed higher bacterial burden and reduced neutrophil recruitment and tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP-2), and CXCL5/LIX expression, along with attenuated histopathological changes in the lungs. Decreased IL-17A levels were observed, along with lower numbers of IL-17A-producing T cells, in RIP2(-/-) mice after infection. RIP2(-/-) mice also show reduced IL-6 and IL-23 levels in the lungs, along with decreased activation of STAT3 after infection. Furthermore, activation of NF-kappa B and mitogen-activated protein kinases (MAPKs) and expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the lungs of infected RIP2(-/-) mice were attenuated following infection. Although neutrophil mobilization to the blood was impaired in RIP2(-/-) mice following infection, the expression of CD62P, CD11a/18, CD11b, and CXCR2 on blood and lung neutrophils was not altered between infected wild-type (WT) and RIP2(-/-) mice. Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood.