MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation
MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation
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DOI：
10.1096/fj.13-248880
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发表时间：
2014-06-01
期刊：
影响因子：
4.8
通讯作者：
Romero, Ignacio Andres
中科院分区：
文献类型：
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作者：
Lopez-Ramirez, Miguel Alejandro;Wu, Dongsheng;Romero, Ignacio Andres
血脑屏障（BBB）功能障碍是多发性硬化症（MS）和中风等神经系统疾病的标志。然而，血脑屏障破坏过程中神经血管功能障碍的分子机制仍然难以捉摸。 MicroRNA (miRNA) 最近已成为致病反应的关键调节因子，尽管它们在中枢神经系统 (CNS) 微血管疾病中的作用很大程度上尚不清楚。我们已经确定 miR-155 是 BBB 神经炎症中的关键 miRNA。 miR-155 在 MS 个体和实验性自身免疫性脑脊髓炎 (EAE) 小鼠的神经血管单位表达。在小鼠中，在 EAE 和脂多糖诱导的急性全身炎症模型中，miR-155 的缺失减少了全身示踪剂的 CNS 外渗。在培养的人脑内皮细胞中，炎症细胞因子强烈而快速地上调 miR-155。 miR-155的上调模拟了细胞因子诱导的连接组织和通透性的改变，而内源性miR-155的抑制部分阻止了细胞因子诱导的通透性的增加。此外，miR-155不仅通过靶向细胞间复合物分子（如annexin-2和claudin-1），还通过靶向粘着斑成分（如DOCK-1和syntenin-1）来调节脑内皮屏障功能。我们提出脑内皮 miR-155 是 BBB 功能的负调节因子，可能构成 CNS 神经炎症性疾病的新治疗靶点。
Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuro-inflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders.