A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia
A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia
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DOI：
10.4049/jimmunol.177.1.583
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Vartanian, Timothy
中科院分区：
文献类型：
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作者：
Lehnardt, Seija;Henneke, Philipp;Vartanian, Timothy
B组链球菌（GBS）是新生儿细菌性脑膜炎和神经系统发病的主要原因。这种常见病原体导致中枢神经系统损伤的细胞和分子机制尚不清楚。我们发现，热灭活的完整GBS以及GBS分泌的一种蛋白质因子（GBS - F）在体外通过依赖TLR2和MyD88的途径激活小鼠小胶质细胞，从而诱导神经元凋亡。小胶质细胞、星形胶质细胞和少突胶质细胞（而非神经元）表达TLR2。GBS以及GBS - F诱导野生型小鼠来源的小胶质细胞合成一氧化氮，但不诱导TLR2（-/-）或MyD88（-/-）小鼠来源的小胶质细胞合成一氧化氮。在添加野生型小胶质细胞的神经元培养物中，神经元死亡是一氧化氮依赖性的。我们首次展示了一种由临床相关细菌诱导的TLR介导的神经元损伤机制。这项研究证明了GBS感染、通过TLR2激活中枢神经系统先天免疫系统以及神经退行性变之间的因果分子关系。我们认为这一过程在很大程度上导致了与新生儿GBS脑膜炎相关的严重发病情况，并可能提供一个潜在的治疗靶点。
Group B Streptococcus (GBS) is a major cause of bacterial meningitis and neurological morbidity in newborn infants. The cellular and molecular mechanisms by which this common organism causes CNS injury are unknown. We show that both heat-inactivated whole GBS and a secreted proteinaceous factor from GBS (GBS-F) induce neuronal apoptosis via the activation of murine microglia through a TLR2-dependent and MyD88-dependent pathway in vitro. Microglia, astrocytes, and oligodendrocytes, but not neurons, express TLR2. GBS as well as GBS-F induce the synthesis of NO in microglia derived from wild-type but not TLR2(-/-) or MyD88(-/-) mice. Neuronal death in neuronal cultures complemented with wild-type microglia is NO-dependent. We show for the first time a TLR-mediated mechanism of neuronal injury induced by a clinically relevant bacterium. This study demonstrates a causal molecular relationship between infection with GBS, activation of the innate immune system in the CNS through TLR2, and neurodegeneration. We suggest that this process contributes substantially to the serious morbidity associated with neonatal GBS meningitis and may provide a potential therapeutic target.