Blockade of microglial adenosine A2A receptor suppresses elevated pressure-induced inflammation, oxidative stress, and cell death in retinal cells
Blockade of microglial adenosine A2A receptor suppresses elevated pressure-induced inflammation, oxidative stress, and cell death in retinal cells
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DOI：
10.1002/glia.23579
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发表时间：
2019-05-01
期刊：
影响因子：
6.2
通讯作者：
Santiago, Ana Raquel
中科院分区：
文献类型：
--
作者：
Aires, Ines Dinis;Bola, Raquel;Santiago, Ana Raquel
青光眼是一种视网膜退行性疾病，其特征是视网膜神经节细胞的丧失和视神经的损伤。最近，我们证明了腺苷A（2A）受体（A(2A)R）拮抗剂可以控制视网膜炎症，并对青光眼模型中的大鼠视网膜细胞提供保护。然而，小胶质细胞对视网膜损伤的确切贡献以及A(2A)R阻断在小胶质细胞中的直接作用尚未得到解决。本研究表明，阻断小胶质细胞A(2A)R可阻止小胶质细胞对高压的反应，足以保护视网膜细胞免受高压引起的死亡。A(2A)R拮抗剂SCH 58261或小胶质细胞中siRNA抑制A(2A)R表达可阻止小胶质细胞对静水压力升高的反应增加。此外，在视网膜神经细胞培养中，A(2A)R拮抗剂减少了小胶质细胞的增殖，以及促炎介质的表达和释放。小胶质细胞消融术可预防血压升高引起的神经细胞死亡。A(2A)R阻断再现了小胶质细胞耗损的影响，表明阻断小胶质细胞中的A(2A)R能够控制青光眼样条件下的神经退行性变。重要的是，在人类器官型视网膜培养中，A(2A)R阻断阻止了活性氧的增加和小胶质细胞由高压引起的形态改变。这些发现表明小胶质细胞是高血压期间视网膜细胞死亡的主要原因，并确定小胶质细胞A(2A)R是控制视网膜神经炎症和防止高血压引起的神经细胞凋亡的治疗靶点。
Glaucoma is a retinal degenerative disease characterized by the loss of retinal ganglion cells and damage of the optic nerve. Recently, we demonstrated that antagonists of adenosine A(2A) receptor (A(2A)R) control retinal inflammation and afford protection to rat retinal cells in glaucoma models. However, the precise contribution of microglia to retinal injury was not addressed, as well as the effect of A(2A)R blockade directly in microglia. Here we show that blocking microglial A(2A)R prevents microglial cell response to elevated pressure and it is sufficient to protect retinal cells from elevated pressure-induced death. The A(2A)R antagonist SCH 58261 or the knockdown of A(2A)R expression with siRNA in microglial cells prevented the increase in microglia response to elevated hydrostatic pressure. Furthermore, in retinal neural cell cultures, the A(2A)R antagonist decreased microglia proliferation, as well as the expression and release of pro-inflammatory mediators. Microglia ablation prevented neural cell death triggered by elevated pressure. The A(2A)R blockade recapitulated the effects of microglia depletion, suggesting that blocking A(2A)R in microglia is able to control neurodegeneration in glaucoma-like conditions. Importantly, in human organotypic retinal cultures, A(2A)R blockade prevented the increase in reactive oxygen species and the morphological alterations in microglia triggered by elevated pressure. These findings place microglia as the main contributors for retinal cell death during elevated pressure and identify microglial A(2A)R as a therapeutic target to control retinal neuroinflammation and prevent neural apoptosis elicited by elevated pressure.