Department of Ophthalmology, Georgia Regents University (GRU), Augusta, GA, USA; Departmet of Biological Sciences, College of Science and Arts, King Abdulaziz University, Rabigh, Saudi Arabia.
J Neuroimmunol. 2013 Nov 15;264(1-2):54-64. doi: 10.1016/j.jneuroim.2013.09.015. Epub 2013 Sep 21.
In traumatic optic neuropathy (TON), apoptosis of retinal ganglion cells is closely related to the local production of reactive oxygen species and inflammatory mediators from activated microglial cells. Adenosine receptor A2A (A2AAR) has been shown to possess anti-inflammatory properties that have not been studied in TON. In the present study, we examined the role of A2AAR in retinal complications associated with TON. Initial studies in wild-type mice revealed that treatment with the A2AAR agonist resulted in marked decreases in the TON-induced microglial activation, retinal cell death and releases of reactive oxygen species and pro-inflammatory cytokines TNF-α and IL-6. To further assess the role of A2AAR in TON, we studied the effects of A2AAR ablation on the TON-induced retinal abnormalities. A2AAR-/- mice with TON showed a significantly higher mRNA level of TNF-α, Iba1-1 in retinal tissue, and ICAM-1 expression in retinal sections compared with wild-type mice with TON. To explore a potential mechanism by which A2AAR-signaling regulates inflammation in TON, we performed additional studies using hypoxia- or LPS-treated microglial cells as an in vitro model for TON. Activation of A2AAR attenuates hypoxia or LPS-induced TNF-α release and significantly repressed the inflammatory signaling, ERK in the activated microglia. Collectively, this work provides pharmacological and genetic evidence for A2AAR signaling as a control point of cell death in TON and suggests that the retinal protective effect of A2AAR is mediated by attenuating the inflammatory response that occurs in microglia via interaction with MAPKinase pathway.
在创伤性视神经病变（TON）中，视网膜神经节细胞的凋亡与激活的小胶质细胞中活性氧和炎症介质的局部产生密切相关。已经表明，腺苷受体 A2A（A2AAR）具有抗炎特性，但尚未在 TON 中进行研究。在本研究中，我们研究了 A2AAR 在与 TON 相关的视网膜并发症中的作用。在野生型小鼠中的初步研究表明，用 A2AAR 激动剂治疗可显著减少 TON 诱导的小胶质细胞激活、视网膜细胞死亡以及活性氧和促炎细胞因子 TNF-α和 IL-6 的释放。为了进一步评估 A2AAR 在 TON 中的作用，我们研究了 A2AAR 缺失对 TON 诱导的视网膜异常的影响。与 TON 野生型小鼠相比，TON 中 A2AAR-/- 小鼠的视网膜组织中 TNF-α和 Iba1-1 的 mRNA 水平以及视网膜切片中的 ICAM-1 表达明显更高。为了探索 A2AAR 信号调节 TON 中炎症的潜在机制，我们使用缺氧或 LPS 处理的小胶质细胞作为 TON 的体外模型进行了额外的研究。A2AAR 的激活可减轻缺氧或 LPS 诱导的 TNF-α释放，并显著抑制炎症信号转导，即激活的小胶质细胞中的 ERK。总之，这项工作提供了药理学和遗传学证据，表明 A2AAR 信号作为 TON 中细胞死亡的控制点，并表明 A2AAR 的视网膜保护作用是通过与 MAPKinase 途径相互作用来减轻小胶质细胞中发生的炎症反应来介导的。
