School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Brain Behav Immun. 2020 Feb;84:59-71. doi: 10.1016/j.bbi.2019.11.008. Epub 2019 Nov 18.
Neuroinflammation is a common pathological feature of many brain diseases and is a key mediator of blood-brain barrier (BBB) breakdown and neuropathogenesis. Adenosine is an endogenous immunomodulator, whose brain extracellular level is tightly controlled by equilibrative nucleoside transporters-1 (ENT1) and ENT2. This study was aimed to investigate the role of ENTs in the modulation of neuroinflammation and BBB function. The results showed that mRNA level of Ent2 was significantly more abundant than that of Ent1 in the brain (hippocampus, cerebral cortex, striatum, midbrain, and cerebellum) of wild-type (WT) mice. Ent2 mice displayed higher extracellular adenosine level in the hippocampus than their littermate controls. Repeated lipopolysaccharide (LPS) treatment induced microglia activation, astrogliosis and upregulation of proinflammatory cytokines, along with aberrant BBB phenotypes (including reduced tight junction protein expression, pericyte loss, and immunoglobulin G extravasation) and neuronal apoptosis in the hippocampus of WT mice. Notably, Ent2 mice displayed significant resistance to LPS-induced neuroinflammation, BBB breakdown, and neurotoxicity. These findings suggest that Ent2 is critical for the modulation of brain adenosine tone and deletion of Ent2 confers protection against LPS-induced neuroinflammation and neurovascular-associated injury.
神经炎症是许多脑部疾病的共同病理特征，是血脑屏障（BBB）破坏和神经发病机制的关键介质。腺苷是一种内源性免疫调节剂，其脑细胞外水平由平衡核苷转运蛋白-1（ENT1）和 ENT2 严格控制。本研究旨在探讨 ENTs 在神经炎症和 BBB 功能调节中的作用。结果表明，在野生型（WT）小鼠的大脑（海马体、大脑皮层、纹状体、中脑和小脑）中，Ent2 的 mRNA 水平明显高于 Ent1。Ent2 小鼠的海马体外腺苷水平高于其同窝对照。反复脂多糖（LPS）处理诱导小胶质细胞激活、星形胶质细胞增生和促炎细胞因子上调，以及海马体 BBB 表型异常（包括紧密连接蛋白表达减少、周细胞丢失和免疫球蛋白 G 外渗）和神经元凋亡。值得注意的是，Ent2 小鼠对 LPS 诱导的神经炎症、BBB 破坏和神经毒性具有显著的抗性。这些发现表明，Ent2 对于调节大脑腺苷水平至关重要，而 Ent2 的缺失可防止 LPS 诱导的神经炎症和神经血管相关损伤。
