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.

中文翻译：

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平衡核苷转运蛋白 2 的缺失保护小鼠免受脂多糖诱导的神经炎症和血脑屏障功能障碍

神经炎症是许多脑部疾病的常见病理特征，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，其脑细胞外水平受到平衡核苷转运蛋白-1 (ENT1) 和 ENT2 的严格控制。本研究旨在研究耳鼻喉科在调节神经炎症和 BBB 功能中的作用。结果表明，在野生型（WT）小鼠的大脑（海马、大脑皮层、纹状体、中脑和小脑）中，Ent2 的 mRNA 水平显着高于 En​​t1。Ent2-/- 小鼠的海马体中细胞外腺苷水平高于其同窝对照小鼠。重复脂多糖 (LPS) 处理诱导小胶质细胞活化，星形胶质细胞增生和促炎细胞因子的上调，以及异常 BBB 表型（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 WT 小鼠海马中的神经元凋亡。值得注意的是，Ent2-/- 小鼠对 LPS 诱导的神经炎症、BBB 分解和神经毒性表现出显着的抵抗力。这些发现表明 Ent2 对脑腺苷张力的调节至关重要，而 Ent2 的缺失可保护免受 LPS 诱导的神经炎症和神经血管相关损伤。Ent2-/- 小鼠对 LPS 诱导的神经炎症、BBB 分解和神经毒性表现出显着的抵抗力。这些发现表明 Ent2 对脑腺苷张力的调节至关重要，而 Ent2 的缺失可保护免受 LPS 诱导的神经炎症和神经血管相关损伤。Ent2-/- 小鼠对 LPS 诱导的神经炎症、BBB 分解和神经毒性表现出显着的抵抗力。这些发现表明 Ent2 对脑腺苷张力的调节至关重要，而 Ent2 的缺失可保护免受 LPS 诱导的神经炎症和神经血管相关损伤。