Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns
Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns
复制标题
DOI：
10.4049/jimmunol.176.11.6802
复制
发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Kielian, Tammy
中科院分区：
文献类型：
--
作者：
Esen, Nilufer;Kielian, Tammy
小胶质细胞是CNS实质的先天性免疫效应细胞，表达TLR，其识别被称为病原体相关分子模式（PAMP）的微生物的保守基序。除了TLR3之外，迄今为止鉴定的所有TLR都使用共同的衔接蛋白MyD88来阻断激活信号。最近，我们报道了小胶质细胞激活革兰氏阳性菌金黄色葡萄球菌没有完全减弱后TLR2消融，表明参与额外的受体。评估替代性TLR在小胶质细胞对S.金黄色葡萄球菌及其细胞壁产物肽聚糖以及革兰氏阴性PAMP LPS，我们评估了来自MyD88敲除（KO）和野生型小鼠的原代小胶质细胞。S.金黄色葡萄球菌和肽聚糖刺激的小胶质细胞是MyD88依赖性的，如MyD88 KO细胞中细胞因子产生的完全抑制所揭示的。此外，额外的模式识别受体，包括TLR9，正五聚蛋白-3，和凝集素样氧化LDL受体-1的表达，调节，部分，通过MyD88依赖性的方式证明了这些受体在MyD88 KO小胶质细胞的表达减弱。在LPS刺激的MyD88 KO细胞中，小胶质细胞活化仅被部分抑制，这表明参与了MyD88非依赖性途径。总的来说，这些发现揭示了小胶质细胞对不同细菌病原体的反应的复杂机制，其通过MyD88依赖性和非依赖性途径发生。
Microglia, the innate immune effector cells of the CNS parenchyma, express TLR that recognize conserved motifs of microorganisms referred to as pathogen-associated molecular patterns (PAMP). All TLRs identified to date, with the exception of TLR3, use a common adaptor protein, MyD88, to transduce activation signals. Recently, we reported that microglial activation in response to the Gram-positive bacterium Staphylococcus aureus was not completely attenuated following TLR2 ablation, suggesting the involvement of additional receptors. To assess the functional role of alternative TLRs in microglial responses to S. aureus and its cell wall product peptidoglycan as well as the Gram-negative PAMP LPS, we evaluated primary microglia from MyD88 knockout (KO) and wild-type mice. The induction of TNF-alpha, IL-12 p40, and MIP-2 (CXCL2) expression by S. aureus- and peptidoglycan-stimulated microglia was MyD88 dependent, as revealed by the complete inhibition of cytokine production in MyD88 KO cells. In addition, the expression of additional pattern recognition receptors, including TLR9, pentraxin-3, and lectin-like oxidized LDL receptor-1, was regulated, in part, via a MyD88-dependent manner as demonstrated by the attenuated expression of these receptors in MyD88 KO microglia. Microglial activation was only partially inhibited in LPS-stimulated MyD88 KO cells, suggesting the involvement of MyD88-independent pathways. Collectively, these findings reveal the complex mechanisms for microglia to respond to diverse bacterial pathogens, which occur via both MyD88-dependent and -independent pathways.