Contribution of Toll-like receptors to the innate immune response to Gram-negative and Gram-positive bacteria
Contribution of Toll-like receptors to the innate immune response to Gram-negative and Gram-positive bacteria
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DOI：
10.1182/blood-2006-06-032961
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发表时间：
2007-02-15
期刊：
影响因子：
20.3
通讯作者：
Pugin, Jerome
中科院分区：
文献类型：
--
作者：
Elson, Greg;Dunn-Siegrist, Irene;Pugin, Jerome
细菌的先天识别是激活炎症和凝血的关键步骤，它依赖于病原体相关分子模式(PAMP)与Toll样受体(TLRs)和CD14的连接。当细胞遇到表达几个PAMP的整个细菌时，主要的受体被激活，但定义不够明确。在这里，我们用典型的革兰氏阴性和革兰氏阳性细菌刺激了各种人类细胞。使用TLR转基因细胞和针对TLRs、MD-2和CD14的特异性单抗评估对整个细菌的受体依赖反应。肠杆菌以TLR4/MD2依赖的方式激活白细胞和包膜细胞，很可能是通过脂多糖(LPS)。在高细菌接种量下观察到TLR2的激活，并且在表达TLR2但不表达TLR4的上皮细胞中观察到TLR2的激活。铜绿假单胞菌通过TLR2和TLR4/MD-2刺激细胞。革兰氏阳性细菌只在高浓度时激活细胞，部分依赖于TLR2，但不依赖TLR4/MD2。TLR或CD14中和均可阻断对所有受试菌株的激活，但全血中的部分革兰氏阳性菌株除外。这项研究确定了参与对整个细菌的反应的主要TLRs。它还验证了细菌病原体对宿主细胞的激活可以通过抗TLR4、-TLR2和-CD14单抗在治疗上减少的概念。
Innate recognition of bacteria is a key step in the activation of inflammation and coagulation, and it is dependent on pathogen-associated molecular pattern (PAMP) ligation to Toll-like receptors (TLRs) and CD14. The dominant receptors activated when cells encounter a whole bacterium, which express several PAMPs, are poorly defined. Herein, we have stimulated various human cells with prototypic Gram-negative and Gram-positive bacteria. Receptor-dependent responses to whole bacteria were assessed using both TLR-transfected cells and specific monoclonal antibodies against TLRs, MD-2, and CD14. Enterobacteria-activated leukocytes and enclothelial cells in a TLR4/MD2-dependent manner, most likely via lipopolysaccharide (LPS). TLR2 activation was observed with a high bacterial inoculum, and in epithelial cells expressing TLR2 but not TLR4. Pseudomonas aerurginosa stimulated cells by both TLR2 and TLR4/MD-2. Gram-positive bacteria activated cells only at high concentrations, in a partially TLR2-dependent but TLR4/MD2-independent manner. Either TLR or CD14 neutralization blocked activation to all bacterial strains tested with the exception of some Gram-positive strains in whole blood in which partial inhibition was noted. This study identifies dominant TLRs involved in responses to whole bacteria. It also validates the concept that host cell activation by bacterial pathogens can be therapeutically reduced by anti-TLR4, -TLR2, and -CD14 mAbs.