The Alternative Complement System Mediates Cell Death in Retinal Ischemia Reperfusion Injury.
The Alternative Complement System Mediates Cell Death in Retinal Ischemia Reperfusion Injury.
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DOI：
10.3389/fnmol.2018.00278
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发表时间：
2018
影响因子：
4.8
通讯作者：
Connor KM
中科院分区：
文献类型：
--
作者：
Inafuku S;Klokman G;Connor KM
缺血再灌注（IR）损伤会诱导视网膜细胞死亡并导致视力障碍。先前的研究表明，补体级联在多种全身性疾病的 IR 损伤中发挥着关键作用。然而，补体途径在缺血性视网膜中的作用尚未得到研究。本研究的目的是确定替代补体级联是否在视网膜 IR 损伤中发挥作用，并确定该途径的哪些成分介导 IR 损伤引起的视网膜变性。为了实现这一目标，我们利用了视网膜IR损伤的小鼠模型，其中眼内压（IOP）升高45分钟，使视网膜血管塌陷并诱导视网膜缺血，然后IOP正常化并随后再灌注。我们发现补体抑制剂补体受体1相关基因/蛋白-y (Crry)、Cd55和Cd59a的mRNA表达在IR后下调。此外，补体成分 3 (C3−/−) 和补体因子 b (Fb−/−) 的基因缺失可减少 IR 诱导的视网膜细胞凋亡。由于血管功能障碍是 IR 损伤的核心，我们还评估了补体在剪切应力模型中的作用。在人视网膜内皮细胞 (HREC) 中，剪切应力上调补体抑制剂 Cd46、Cd55 和 Cd59，并抑制补体介导的细胞死亡，表明在 IR 损伤中常见的血管血流缺乏，导致补体介导的视网膜脉管系统攻击。这些结果表明，在视网膜IR损伤中，替代补体系统通过补体抑制剂的抑制而被激活，导致血管功能障碍和神经元细胞死亡。
Ischemia reperfusion (IR) injury induces retinal cell death and contributes to visual impairment. Previous studies suggest that the complement cascade plays a key role in IR injury in several systemic diseases. However, the role of the complement pathway in the ischemic retina has not been investigated. The aim of this study is to determine if the alternative complement cascade plays a role in retinal IR injury, and identify which components of the pathway mediate retinal degeneration in response to IR injury. To accomplish this, we utilized the mouse model of retinal IR injury, wherein the intraocular pressure (IOP) is elevated for 45 min, collapsing the retinal blood vessels and inducing retinal ischemia, followed by IOP normalization and subsequent reperfusion. We found that mRNA expression of complement inhibitors complement receptor 1-related gene/protein-y (Crry), Cd55 and Cd59a was down-regulated after IR. Moreover, genetic deletion of complement component 3 (C3−/−) and complement factor b (Fb−/−) decreased IR-induced retinal apoptosis. Because vascular dysfunction is central to IR injury, we also assessed the role of complement in a model of shear stress. In human retinal endothelial cells (HRECs), shear stress up-regulated complement inhibitors Cd46, Cd55, and Cd59, and suppressed complement-mediated cell death, indicating that a lack of vascular flow, commonly observed in IR injury, allows for complement mediated attack of the retinal vasculature. These results suggested that in retinal IR injury, the alternative complement system is activated by suppression of complement inhibitors, leading to vascular dysfunction and neuronal cell death.
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