An adenosine A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-B and CREB phosphorylation
An adenosine A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-B and CREB phosphorylation
复制标题
腺苷 A1R-A2aR 失衡调节低葡萄糖/缺氧诱导的小胶质细胞激活，从而通过 NF-κB 和 CREB 磷酸化导致少突胶质细胞损伤。
DOI：
10.3892/ijmm.2018.3546
复制
发表时间：
2018-06-01
影响因子：
5.4
通讯作者：
Xie, Peng
中科院分区：
文献类型：
--
作者：
Huang, Wen;Bai, Shunjie;Xie, Peng
小胶质细胞活化介导的对少突胶质细胞的炎性损伤是缺血性白色病变病因学中的关键步骤。腺苷A1受体（A1 R）和腺苷A2 a受体（A2 aR）已被报道调节小胶质细胞的活化，然而，其潜在的机制仍不清楚。因此，本研究使用暴露于低糖/缺氧的小胶质细胞/少突胶质细胞共培养模型，并用A1 R和A2 aR的激动剂/拮抗剂处理，以研究A1 R和A2 aR的作用。A1 R和A2 aR表达和炎性细胞因子分泌的小胶质细胞，少突胶质细胞损伤，暴露后的变化进行了检查。低糖/缺氧诱导A1 R升高高于A2 aR。此外，A1 R的激活抑制A2 aR蛋白的表达，反之亦然。A1受体拮抗剂DPCPX（100 nM）和A2 aR激动剂CGS 21680（100 nM）抑制小胶质细胞活化，减少炎性细胞因子的产生，减轻少突胶质细胞损伤，沿着磷酸化核因子（NF）-B和环磷酸腺苷反应元件结合蛋白（CREB）水平升高。这些数据表明，A1 R-A2 aR失衡能够通过改变NF-B和CREB磷酸化来调节低葡萄糖诱导的小胶质细胞活化和细胞免疫应答。这表明A1 R-A2 aR的再平衡是治疗白色物质损伤的有前景的方法。
Microglial activation-mediated inflammatory damage to oligodendrocytes is a key step in the etiology of ischemic white matter lesions. The adenosine A1 receptor (A1R) and adenosine A2a receptor (A2aR) have been reported to regulate the activation of microglia, however, the underlying mechanisms remain elusive. Thus, the present study used a microglia/oligodendrocyte co-culture model exposed to low glucose/hypoxia, and treated with agonists/antagonists of A1R and A2aR to investigate the role of A1R and A2aR. Changes in A1R and A2aR expression and inflammatory cytokine secretion by the microglia, and oligodendrocyte damage, after exposure were examined. Low glucose/hypoxia induced a higher elevation of A1R than A2aR. In addition, activation of A1R inhibited A2aR protein expression and vice versa. The A1R antagonist DPCPX (100 nM) and A2aR agonist CGS 21680 (100 nM) inhibited microglial activation, reduced the production of inflammatory cytokines and attenuated oligodendrocyte damage, along with elevating the levels of phosphorylated nuclear factor (NF)-B and cyclic adenosine monophosphate response element binding protein (CREB). These data indicate that an A1R-A2aR imbalance is able to modulate low glucose-induced microglial activation and the cellular immune response through altering NF-B and CREB phosphorylation. This suggests that rebalancing A1R-A2aR is a promising approach for treating white matter injury.