Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood-Brain Barrier are Modulated by Alpha7 Nicotinic Receptor
Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood-Brain Barrier are Modulated by Alpha7 Nicotinic Receptor
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DOI：
10.1371/journal.pone.0025016
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发表时间：
2011-09-22
期刊：
影响因子：
3.7
通讯作者：
Huang, Sheng-He
中科院分区：
文献类型：
--
作者：
Chi, Feng;Wang, Lin;Huang, Sheng-He
α 7烟碱乙酰胆碱受体（nAChR）是一种重要的炎症调节因子，在易受细菌性脑膜炎影响的海马神经元中大量表达。然而，尚不清楚7 nAChR是否有助于调节这些事件。在这份报告中，α 7 nAChR在宿主防御脑膜炎E。通过使用α 7-缺陷（α 7（-/-））小鼠脑微血管内皮细胞（BMEC）和动物模型系统证明了大肠杆菌感染。体外和体内研究表明，E.在α 7（-/-）BMEC和α 7（-/-）小鼠中，coli K1侵袭和多形核中性粒细胞（PMN）穿过血脑屏障（BBB）的迁移显著减少。尼古丁的刺激在α 7（-/-）细胞和动物中被消除。α 7受体拮抗剂甲基甘草次酸也有同样的阻断作用。紧密连接分子occludin和ZO-1在感染E.与α 7（-/-）细胞和动物相比，在患有脑膜炎的α 7（-/-）小鼠中观察到海马齿状回神经元损伤减少。在患有大肠杆菌的α 7（-/-）小鼠的脑脊液中，促炎细胞因子（IL-1 β、IL-6、TNF α、MCP-1、MIP-1 α和RANTES）和粘附分子（CD 44和ICAM-1）显著减少。大肠杆菌脑膜炎。此外，α 7 nAChR是尼古丁和E. coli K1-增加小鼠BMEC细胞内钙离子浓度。总之，我们的数据表明，α 7 nAChR在宿主防御脑膜炎感染中起着有害的作用，通过调节病原体入侵，PMN招募，钙信号传导和神经元炎症。
Alpha7 nicotinic acetylcholine receptor (nAChR), an essential regulator of inflammation, is abundantly expressed in hippocampal neurons, which are vulnerable to bacterial meningitis. However, it is unknown whether 7 nAChR contributes to the regulation of these events. In this report, an aggravating role of alpha 7 nAChR in host defense against meningitic E. coli infection was demonstrated by using alpha 7-deficient (alpha 7(-/-)) mouse brain microvascular endothelial cells (BMEC) and animal model systems. As shown in our in vitro and in vivo studies, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) were significantly reduced in alpha 7(-/-) BMEC and alpha 7(-/-) mice. Stimulation by nicotine was abolished in the alpha 7(-/-) cells and animals. The same blocking effect was achieved by methyllycaconitine (alpha 7 antagonist). The tight junction molecules occludin and ZO-1 were significantly reduced in the brain cortex of wildtype mice infected with E. coli and treated with nicotine, compared to alpha 7(-/-) cells and animals. Decreased neuronal injury in the hippocampal dentate gyrus was observed in alpha 7(-/-) mice with meningitis. Proinflammatory cytokines (IL-1 beta, IL-6, TNF alpha, MCP-1, MIP-1alpha, and RANTES) and adhesion molecules (CD44 and ICAM-1) were significantly reduced in the cerebrospinal fluids of the alpha 7(-/-) mice with E. coli meningitis. Furthermore, alpha 7 nAChR is the major calcium channel for nicotine-and E. coli K1-increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that alpha 7 nAChR plays a detrimental role in the host defense against meningitic infection by modulation of pathogen invasion, PMN recruitment, calcium signaling and neuronal inflammation.