Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.
Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.
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DOI：
10.1523/jneurosci.4628-11.2012
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发表时间：
2012-03-21
期刊：
影响因子：
--
通讯作者：
Persidsky Y
中科院分区：
文献类型：
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作者：
Ramirez SH;Haskó J;Skuba A;Fan S;Dykstra H;McCormick R;Reichenbach N;Krizbai I;Mahadevan A;Zhang M;Tuma R;Son YJ;Persidsky Y
以前的研究表明，在神经炎症过程中调节受体介导的大麻素系统可以产生有效的神经保护和抗炎作用。然而，在这种情况下，很少有人知道大麻素2型受体（CB 2 R）的选择性激活如何影响脑内皮细胞和血脑屏障（BBB）功能的激活状态。使用人脑组织和原代人脑内皮细胞（BMVEC），我们证明了CB 2 R在炎症损伤过程中高度上调。然后，我们使用LPS诱导的脑炎小鼠模型和高选择性CB 2 R激动剂来检查CB 2 R激动剂是否可以减弱BBB的炎症反应。通过活体显微镜观察显示，施用JWH 133或基于间苯二酚的新型化合物O-1966大大减弱了表面软脑膜血管和深层上升皮质毛细血管后小静脉中的白细胞粘附。用小的和大的荧光示踪剂进行的BBB渗透性评估表明，CB 2 R激动剂在LPS施用后有效地防止屏障渗漏。为了确定CB 2 R激动剂对屏障保护的作用是否不仅仅是由于免疫细胞功能的CB 2 R调节，我们在体外用形成屏障的原代BMVEC测试了激动剂。值得注意的是，添加CB 2 R激动剂增加了跨内皮电阻，并增加了膜组分中存在的紧密连接蛋白的量。此外，CB 2 R激动剂可降低暴露于各种促炎介质的BMVEC中ICAM-1和VCAM-1表面表达的诱导。总之，这些结果表明，药理学CB 2 R配体提供了一种新的策略，在神经炎症的BBB保护。
Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects. However in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood brain barrier (BBB) function. Using human brain tissues and primary human brain endothelial cells (BMVEC) we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 or a novel resorcinol-based compound O-1966, greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending cortical post-capillary venules. BBB permeability assessments with small and large fluorescent tracers showed that CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in-vitro with barrier forming primary BMVEC. Remarkably, the addition of CB2R agonist increased trans-endothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of ICAM-1 and VCAM-1 surface expression in BMVEC exposed to various pro-inflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.