MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS
MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS
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DOI：
10.1093/brain/awh171
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发表时间：
2004-06-01
期刊：
影响因子：
14.5
通讯作者：
Kirschning, CJ
中科院分区：
文献类型：
--
作者：
Koedel, U;Rupprecht, T;Kirschning, CJ
髓样分化因子88（MyD 88）是Toll样受体（TLR）和白细胞介素（IL）-1受体家族成员介导的细胞活化中的重要细胞内信号转导因子。为了表征MyD 88在肺炎球菌脑膜炎中的作用，我们使用了缺乏功能性MyD 88表达的基因靶向小鼠。在脑池内感染后24小时，MyD 88缺陷型小鼠在CNS中显示出显著减少的炎症宿主反应，如CSF细胞增多和细胞因子、趋化因子和补体因子表达减少所证明的。CNS炎症的减少被预后相关CNS并发症（如脑水肿形成）的显著减少所证实。然而，MyD 88缺陷与疾病恶化相关，这似乎可归因于严重的菌血症。这一观点得到了以下意外观察结果的支持：与感染的野生型小鼠相比，感染的MyD 88缺陷型小鼠肺中炎性介质[如促炎细胞因子肿瘤坏死因子α（TNF-α）和CXC趋化因子巨噬细胞炎性蛋白（MIP-2）]的mRNA表达增强，因此支气管肺泡灌洗液中的细胞流入增加。因此，本研究首次证明了MyD 88在CNS内对细菌病原体的免疫激活中的重要作用。然而，MyD 88在启动对肺炎链球菌的免疫应答中所起的作用似乎取决于所涉及的解剖区室。
Myeloid differentiation factor 88 (MyD88) is an essential intracellular signal transducer in Toll-like receptor (TLR) and interleukin (IL)-1 receptor family member-mediated cell activation. In order to characterize the role of MyD88 in pneumococcal meningitis we used gene-targeted mice lacking functional MyD88 expression. At 24 h after intracisternal infection, MyD88- deficient mice displayed a markedly diminished inflammatory host response in the CNS, as evidenced by reduced CSF pleocytosis and expression of cytokines, chemokines and complement factors. The reduced CNS inflammation was paralleled by a marked reduction in the prognostic relevant CNS complications, such as brain oedema formation. Nevertheless, MyD88 deficiency was associated with a worsening of disease which seemed to be attributable to severe bacteraemia. This notion was supported by the unexpected observation that infected MyD88-deficient mice displayed enhanced mRNA expression of inflammatory mediators [such as the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the CXC chemokine macrophage inflammatory protein (MIP-2)] in the lung and consequently increased cell influx in the bronchoalveolar lavage fluid, compared with infected wild-type mice. Thus, the present study demonstrated for the first time an important role of MyD88 in immune activation to bacterial pathogens within the CNS. The role played by MyD88 in mounting an immune response to Streptococcus pneumoniae, however, seems to be dependent on the anatomical compartment involved.