Institute of NeuroImmune Pharmacology, Seton Hall University, 400 South Orange Ave, South Orange, NJ, 07079, USA.
Department of Biological Sciences, Seton Hall University, 400 South Orange Ave, South Orange, NJ, 07079, USA.
J Neuroimmune Pharmacol. 2018 Dec;13(4):498-508. doi: 10.1007/s11481-018-9796-3. Epub 2018 Jul 9.
Ethanol (EtOH), the main ingredient in alcoholic beverages, is well known for its behavioral, physiological, and immunosuppressive effects. There is evidence that EtOH acts through protein targets to exert its physiological effects; however, the mechanisms underlying EtOH's effects on inflammatory processes, particularly at the blood-brain barrier (BBB), are still poorly understood. Transient receptor potential (TRP) channels, the vanguards of human sensory systems, are novel molecular receptors significantly affected by EtOH, and are heavily expressed in brain microvascular endothelial cells (BMVECs), one of the cellular constituents of the BBB. EtOH's actions on endothelial TRP channels could affect intracellular Ca and Mg dynamics, which mediate leukocyte adhesion to endothelial cells and endothelial permeability at the BBB, thus altering immune and inflammatory responses. We examined the basal expression profiles of all 29 known mammalian TRP channels in mouse BMVECs and determined both EtOH concentration- and time-dependent effects on TRP expression using a PCR array. We also generated an in vitro BBB model to examine the involvement of a chosen TRP channel, TRP melastatin 7 (TRPM7), in EtOH-mediated alteration of BBB permeability. With the exception of the akyrin subfamily, members of five TRP subfamilies were expressed in mouse BMVECs, and their expression levels were modulated by EtOH in a concentration-dependent manner. In the in vitro BBB model, TRPM7 antagonists further enhanced EtOH-mediated alteration of BBB permeability. Because of the diversity of TRP channels in BMVECs that regulate cellular processes, EtOH can affect Ca/Mg signaling, immune responses, lysosomal functions as well as BBB integrity.
乙醇（EtOH）是酒精饮料的主要成分，其行为、生理和免疫抑制作用众所周知。有证据表明，EtOH 通过蛋白质靶标发挥其生理作用；然而，EtOH 对炎症过程的影响机制，特别是在血脑屏障（BBB），仍知之甚少。瞬时受体电位（TRP）通道是人类感觉系统的先锋队，是受 EtOH 显著影响的新型分子受体，在脑微血管内皮细胞（BMVEC）中大量表达，BMVEC 是 BBB 的细胞成分之一。EtOH 对内皮 TRP 通道的作用可能会影响细胞内 Ca 和 Mg 动力学，从而介导白细胞与内皮细胞的黏附和内皮通透性，从而改变免疫和炎症反应。我们检查了 29 种已知哺乳动物 TRP 通道在小鼠 BMVEC 中的基础表达谱，并使用 PCR 阵列确定了 EtOH 浓度和时间依赖性对 TRP 表达的影响。我们还生成了体外 BBB 模型，以研究选定的 TRP 通道，TRP melastatin 7（TRPM7），在 EtOH 介导的 BBB 通透性改变中的作用。除了 akyrin 亚家族外，五个 TRP 亚家族的成员在小鼠 BMVEC 中表达，并且它们的表达水平以浓度依赖的方式被 EtOH 调节。在体外 BBB 模型中，TRPM7 拮抗剂进一步增强了 EtOH 介导的 BBB 通透性改变。由于 BMVEC 中调节细胞过程的 TRP 通道的多样性，EtOH 可以影响 Ca/Mg 信号、免疫反应、溶酶体功能以及 BBB 完整性。
