Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier.
Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier.
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脑膜炎大肠杆菌诱导 VEGFA 和 Snail-1 介导血脑屏障破坏
DOI：
10.18632/oncotarget.11696
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发表时间：
2016-09-27
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
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作者：
Yang R;Liu W;Miao L;Yang X;Fu J;Dou B;Cai A;Zong X;Tan C;Chen H;Wang X
大肠杆菌是最常见的革兰氏阴性细菌，能够引起新生儿脑膜炎，这种细菌是随着循环细菌穿透血脑屏障 (BBB) 而发生的。然而，脑膜炎大肠杆菌是否会导致血脑屏障破坏及其潜在机制尚不清楚。我们目前的工作首次强调了 VEGFA 和 Snail-1 在脑膜炎大肠杆菌诱导的 BBB 破坏中的参与及其潜在机制。在这里，我们对引起脑膜炎的大肠杆菌 PCN033 进行了表征，并证明 PCN033 入侵可以通过下调和重塑紧密连接蛋白（TJ 蛋白）来增加 BBB 通透性。这一过程需要 PCN033 感染诱导 VEGFA 和 Snail-1 上调，这涉及 TLR2-MAPK-ERK1/2 信号级联的激活。此外，感染时促炎细胞因子和趋化因子的产生也促进了 VEGFA 和 Snail-1 的上调，从而进一步介导 BBB 破坏。我们在此报告的观察结果直接支持 VEGFA 和 Snail-1 参与脑膜炎大肠杆菌诱导的 BBB 破坏，因此 VEGFA 和 Snail-1 将代表未来临床预防大肠杆菌脑膜炎的重要宿主靶点。
Escherichia coli is the most common Gram-negative bacterium that possesses the ability to cause neonatal meningitis, which develops as circulating bacteria penetrate the blood-brain barrier (BBB). However, whether meningitic E. coli could induce disruption of the BBB and the underlying mechanisms are poorly understood. Our current work highlight for the first time the participation of VEGFA and Snail-1, as well as the potential mechanisms, in meningitic E. coli induced disruption of the BBB. Here, we characterized a meningitis-causing E. coli PCN033, and demonstrated that PCN033 invasion could increase the BBB permeability through downregulating and remodeling the tight junction proteins (TJ proteins). This process required the PCN033 infection-induced upregulation of VEGFA and Snail-1, which involves the activation of TLR2-MAPK-ERK1/2 signaling cascade. Moreover, production of proinflammatory cytokines and chemokines in response to infection also promoted the upregulation of VEGFA and Snail-1, therefore further mediating the BBB disruption. Our observations reported here directly support the involvement of VEGFA and Snail-1 in meningitic E. coli induced BBB disruption, and VEGFA and Snail-1 would therefore represent the essential host targets for future prevention of clinical E. coli meningitis.