Complement Deposition and Microglial Activation in the Outer Retina in Light-Induced Retinopathy: Inhibition by a 5-HT1A Agonist
Complement Deposition and Microglial Activation in the Outer Retina in Light-Induced Retinopathy: Inhibition by a 5-HT1A Agonist
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DOI：
10.1167/iovs.10-6418
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发表时间：
2011-10-01
影响因子：
4.4
通讯作者：
Romano, Carmelo
中科院分区：
文献类型：
--
作者：
Collier, Robert J.;Wang, Yu;Romano, Carmelo
目的。越来越多的证据支持补体在年龄相关性黄斑变性 (AMD) 发病机制中的作用。本研究评估了光诱导视网膜病变模型中的视网膜小胶质细胞、T 淋巴细胞和补体沉积。研究了血清素（5-羟色胺，5-HT1A）激动剂对这些过程的影响。方法。大鼠在接受 6 小时的蓝光照射之前先进行 24 小时的暗适应。一些动物预先皮下注射 AL-8309A。在光照后的不同时间评估视网膜。石蜡切片用小胶质细胞标记物 (Iba1)、T 淋巴细胞标记物 (CD3) 和补体成分 C1q、C3、B 因子、H 因子和膜攻击复合物 (MAC) 的抗体进行染色。结果。光照会导致光感受器和 RPE 大量损失。小胶质细胞的强烈激活和向外视网膜的迁移迅速发生。没有发生大量的 T 淋巴细胞募集。补体旁路途径被强烈激活，导致C3、B因子、H因子和MAC在光损伤区域沉积。服用 AL-8309A 可以预防视网膜病变，并减少外视网膜中小胶质细胞的激活/募集和补体沉积。结论。在暴露于蓝光的视网膜中，小胶质细胞被激活并向外视网膜迁移，而 T 淋巴细胞反应却很小。先天免疫系统被显着激活，光照后，大量补体沉积在视网膜外层。 AL-8309A 阻止了这种补体沉积。该模型可用于评估补体抑制剂和其他眼用神经保护剂。 AL-8309 正在临床评估中，可能有助于治疗 AMD。 （投资眼科可见科学。2011；52：8108-8116）DOI：10.1167/iovs.10-6418
PURPOSE. Increasing evidence supports a role for complement in the pathogenesis of age-related macular degeneration (AMD). This study evaluated retinal microglia, T-lymphocytes, and complement deposition in a light-induced retinopathy model. The effect of a serotonin (5-hydroxytryptamine, 5-HT1A) agonist on these processes was investigated.METHODS. Rats were dark adapted for 24 hours before a 6-hour blue light exposure. Some animals were predosed subcutaneously with AL-8309A. Retinas were evaluated at different times after light exposure. Paraffin sections were stained with antibody for a microglial marker (Iba1), a T-lymphocyte marker (CD3), and complement components C1q, C3, factor B, factor H, and membrane attack complex (MAC).RESULTS. Light exposure resulted in substantial photoreceptor and RPE loss. Robust microglia activation and migration to the outer retina occurred rapidly. Substantial T-lymphocyte recruitment did not occur. Complement alternative pathway was strongly activated, resulting in the deposition of C3, factor B, factor H, and MAC in the area of photic lesions. Dosing with AL-8309A prevented retinal lesions and decreased microglia activation/recruitment and complement deposition in the outer retina.CONCLUSIONS. In blue light exposed retinas, microglia were activated and migrated toward the outer retina, whereas a T-lymphocyte response was minimal. The innate immune system was markedly activated, with substantial complement deposition in the outer retina after light exposure. This complement deposition was prevented by AL-8309A. This model may be useful in the evaluation of complement inhibitors and other neuroprotectants intended for ocular use. AL-8309 is under evaluation in the clinic and may be useful in the treatment of AMD. (Invest Ophthalmol Vis Sci. 2011;52:8108-8116) DOI: 10.1167/iovs.10-6418