Role played by Toll-like receptors 2 and 4 in lipoteichoic acid-induced lung inflammation and coagulation
Role played by Toll-like receptors 2 and 4 in lipoteichoic acid-induced lung inflammation and coagulation
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DOI：
10.1086/524873
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发表时间：
2008-01-15
影响因子：
6.4
通讯作者：
van der Poll, Tom
中科院分区：
文献类型：
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作者：
Dessing, Mark C.;Schouten, Marcel;van der Poll, Tom
背景肺炎链球菌的细胞壁由脂磷壁酸（LTA）组成，当肺炎球菌被宿主免疫系统或抗生素治疗杀死时释放。由于其促炎特性，过量LTA的释放与严重革兰氏阳性感染的毒性后遗症有关。几项体外研究表明，LTA被Toll样受体（TLR）2和CD14识别。我们的目的是研究S.目的：探讨TLR2、TLR4和CD14在肺炎链球菌LTA中的作用。将高度纯化的肺炎球菌LTA鼻内接种野生型（WT）、TLR2敲除（KO）、TLR4 KO、TLR2 X 4双KO和CD14 KO小鼠。LTA诱导剂量依赖性炎症反应，并以TLR2依赖性方式激活凝血和纤溶途径。令人惊讶的是，与WT小鼠相比，TLR4基因敲除小鼠的肺部炎症和凝血反应也有所减弱，这可能是由于通过LTA诱导的内源性介质释放缺乏TLR4信号传导。肺炎球菌LTA通过TLR2依赖性途径在体内诱导肺部的严重炎症反应和凝血途径的激活，这可能被内源性TLR4配体放大。
Background. The cell wall of Streptococcus pneumoniae consists of lipoteichoic acid (LTA), which is released when pneumococci are killed by either the host immune system or antibiotic treatment. Release of excessive amounts of LTA has been implicated in the toxic sequelae of severe gram-positive infection by virtue of its proinflammatory properties. Several in vitro studies have shown that LTA is recognized by Toll-like receptor (TLR) 2 and CD14. Our objective here was to investigate the inflammatory properties of S. pneumoniae LTA in vivo and the role played by TLR2, TLR4, and CD14 therein.Methods. Wild-type (WT), TLR2 knockout (KO), TLR4 KO, TLR2 X 4 double-KO, and CD14 KO mice were intranasally inoculated with highly purified pneumococcal LTA.Results. LTA induced a dose-dependent inflammatory response and activation of the coagulation and fibrinolytic pathways in a TLR2-dependent fashion. Surprisingly, TLR4 KO mice also displayed a somewhat diminished pulmonary inflammatory and coagulant response compared with WT mice, possibly as a result of absent TLR4 signaling through LTA-induced release of endogenous mediators.Conclusion. Pneumococcal LTA induces a profound inflammatory response and activation of the coagulation pathway in the lungs in vivo through a TLR2-dependent route, which likely is amplified by endogenous TLR4 ligands.