Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium
Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium
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DOI：
10.1177/1352458517735189
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发表时间：
2018-12-01
影响因子：
5.8
通讯作者：
Schwab, Nicholas
中科院分区：
文献类型：
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作者：
Breuer, Johanna;Herich, Sebastian;Schwab, Nicholas
目的：富马酸二甲酯（DMF）用于治疗复发缓解型多发性硬化症（MS）。在这里，我们研究了DMF及其代谢产物富马酸单甲基（MMF）在体内对（炎症）血脑屏障（BBB）的影响。方法：采用原代人脑源性微血管内皮细胞（HBMECs）联合dmf治疗的MS患者外周血单个核细胞（PBMCs），分析富马酸酯的作用。结果：mmf与脑内皮细胞结合可激活核因子（红细胞衍生2）相关因子2 （Nrf2）诱导的血管细胞粘附分子1 （VCAM-1）下调。这可能是通过g蛋白偶联受体（GPCR）羟基羧酸受体2 （HCA(2)）介导的，HCA(2)是MMF的已知分子靶点，我们可以证明其在hbmec上的表达和调控。DMF在体内通过选择性地减少MS患者高表达整合素的记忆T细胞，导致VCAM-1的配体极晚抗原4 （vca -4）的表达强烈降低，这可能是由于NF κ b的反定位减少抑制了它们的成熟。dmf介导的内皮侧VCAM-1的下调和淋巴细胞侧具有迁移表型的T细胞的减少导致T细胞粘附到活化内皮的协同减少，因此，减少了MS背景下血脑屏障的迁移。
Objective: Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood-brain barrier (BBB). Methods: Effects of fumaric acid esters were analyzed using primary human brain-derived microvascular endothelial cells (HBMECs) in combination with peripheral blood mononuclear cells (PBMCs) derived from DMF-treated MS patients. Results: MMF-binding to brain endothelium cells leads to activation of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2)-induced downregulation of vascular cell adhesion molecule 1 (VCAM-1). This might be mediated via the G-protein-coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCA(2)), a known molecular target of MMF, as we could demonstrate its expression and regulation on HBMECs. DMF treatment in vivo led to a strongly reduced expression of VCAM-1's ligand very late antigen 4 (VLA-4) by selectively reducing integrin high-expressing memory T cells of MS patients, potentially due to inhibition of their maturation by reduced trans-localization of NF kappa B. Conclusion: DMF-mediated VCAM-1 downregulation on the endothelial side and reduction in T cells with a migratory phenotype on the lymphocyte side result in a synergistic reduction in T-cell adhesion to activated endothelium and, therefore, to reduced BBB transmigration in the setting of MS.