Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseudomonas aeruginosa
Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseudomonas aeruginosa
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DOI：
10.4049/jimmunol.177.1.538
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Worthen, G. Scott
中科院分区：
文献类型：
--
作者：
Jeyaseelan, Samithamby;Young, Scott K.;Worthen, G. Scott
细菌性肺炎是死亡的主要原因，与广泛的中性粒细胞积聚有关。与该疾病相关的主要病原体包括无鞭毛肺炎克雷伯菌（Kp）和鞭毛铜绿假单胞菌（Pa）。TLR是先天免疫防御所必需的。TIRAP（bar下的（T）奥尔特/bar下的（I）巴尔-1（R））是TLR 1、TLR 2、TLR 4和TLR 6信号传导中的衔接子，而MyD 88是所有TLR的衔接子。然而，TIRAP在肺防御Kp或Pa中的重要性尚未得到研究。为了证明TIRAP的作用，用Kp或Pa对TIRAP缺陷型和野生型同窝仔进行肠道内接种。我们发现TIRAP（-/-）小鼠具有显著的死亡率、肺中更高的细菌负荷以及在Kp攻击后增强的传播。此外，在TIRAP（-/-）小鼠的肺中，KP诱导的中性粒细胞隔离、组织病理学和MIP-2、TNF-α、IL-6和LIX（barC趋化因子下脂多糖诱导的C（X））产生减弱。相比之下，TIRAP对于Pa诱导的死亡率、肺细菌负荷、细菌传播、嗜中性粒细胞积累或组织病理学不是必需的，但对于MIP-2、TNF-α和IL-6产生是必需的，而不是LIX产生。然而，Kp和Pa诱导的中性粒细胞流入都是MyD 88依赖性的。为了确定与Pa诱导的中性粒细胞积聚相关的机制，我们用Pa的鞭毛蛋白C突变体（Pa Delta fliC）或纯化的鞭毛蛋白（TLR 5激动剂）接种小鼠。Pa Delta fliC诱导的中性粒细胞隔离和LIX表达依赖于TIRAP，而鞭毛蛋白诱导的中性粒细胞流入和LIX表达独立于TIRAP。这些新的发现阐明了TIRAP在肺防御中的病原体特异性作用，并表明TLR 5通过LIX产生对Pa诱导的中性粒细胞流入起着至关重要的作用。
Bacterial pneumonia is a leading cause of mortality and is associated with extensive neutrophil accumulation. Major pathogens associated with this disease include nonflagellated Klebsiella pneumoniae (Kp) and flagellated Pseudomonas aeruginosa (Pa). TLRs are essential for innate immune defense. TIRAP ((T) under bar olt/(I) under barL-1 (R) under bar domain-containing adaptor protein) is an adaptor in TLR1, TLR2, TLR4, and TLR6 signaling, whereas MyD88 is an adaptor for all TLRs. However, the importance of TIRAP in pulmonary defense against Kp or Pa has not been examined. To demonstrate the role of TIRAP, TIRAP-deficient and wild-type littermates were intratracheally inoculated with Kp or Pa. We found that TIRAP(-/-) mice had substantial mortality, higher bacterial burden in the lungs, and enhanced dissemination following Kp challenge. Furthermore, Kp-induced neutrophil sequestration, histopathology, and MIP-2, TNF-alpha, IL-6, and LIX (lipopolysaccharide-induced C (X) under barC chemokine) production were attenuated in the lungs of TIRAP(-/-) mice. In contrast, TIRAP is not required for Pa-induced mortality, pulmonary bacterial burden, bacterial dissemination, neutrophil accumulation, or histopathology, yet it is necessary for MIP-2, TNF-a, and IL-6 production, but not LIX production. However, both Kp- and Pa-induced neutrophil influxes are MyD88 dependent. To determine the mechanisms associated with Pa-induced neutrophil accumulation, we inoculated mice with a flagellin C mutant of Pa (Pa Delta fliC) or purified flagellin, a TLR5 agonist. Pa Delta fliC-induced neutrophil sequestration and LIX expression are dependent on TIRAP, whereas flagellin-induced neutrophil influx and LIX expression are independent of TIRAP. These novel findings illustrate a pathogen-specific role for TIRAP in pulmonary defense and suggest that TLR5 plays an essential role for Pa-induced neutrophil influx via LIX production.