Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis
Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis
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DOI：
10.1073/pnas.1008816107
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发表时间：
2010-11-02
影响因子：
11.1
通讯作者：
Teuscher, Cory
中科院分区：
文献类型：
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作者：
Lu, Changming;Diehl, Sean A.;Teuscher, Cory
血脑屏障（BBB）的破坏是实验性自身免疫性脑脊髓炎（EAE）和多发性硬化症发展的基础。环境因素，如百日咳杆菌，被认为使中央内皮细胞对生物胺如组胺敏感，从而导致血脑屏障通透性增加。百日咳诱导的组胺致敏（Bphs）是一种由组胺H-1受体（Hrh1/H1R）控制的EAE单基因中间表型。我们在Hrh1-KO（H1RKO）小鼠内皮细胞中转基因过表达H1R，以测试内皮细胞H1R在Bphs和EAE中的直接作用。出乎意料的是，在血管性血友病因子启动子（H1RKO- vwf (H1R) Tg）的控制下，表达内皮细胞H1R的转基因H1RKO小鼠具有bph抗性。此外，与H1RKO小鼠相比，H1RKO- vwf (H1R) Tg小鼠血脑屏障通透性降低，对EAE的保护作用增强。因此，与普遍的假设相反，我们的研究结果表明，内皮细胞H1R的表达降低了血脑屏障的通透性，这表明内皮细胞H1R信号传导可能在维持脑血管完整性中起重要作用。
Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertus-sis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine H-1 receptor (Hrh1/H1R). Here, we transgenically overexpressed H1R in endothelial cells of Hrh1-KO(H1RKO) mice to test the role of endothelial H1R directly in Bphs and EAE. Unexpectedly, transgenic H1RKO mice expressing endothelial H1R under control of the von Willebrand factor promoter (H1RKO-vWF(H1R) Tg) were Bphs-resistant. Moreover, H1RKO-vWF(H1R) Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with H1RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H1R expression reduces BBB permeability, suggesting that endothelial H1R signaling may be important in the maintenance of cerebrovascular integrity.