CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration
CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration
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DOI：
10.4049/jimmunol.178.3.1783
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Bora, Puran S.
中科院分区：
文献类型：
--
作者：
Bora, Nalini S.;Kaliappan, Sankaranarayanan;Bora, Puran S.
我们已经证明，通过激活替代途径形成的膜攻击复合物（MAC）在激光诱导的脉络膜新生血管（CNV）中发挥着核心作用。本研究旨在了解补体调节蛋白 CD59 在此模型中的作用，该蛋白控制 MAC 组装和功能。使用氩激光对 C5713L/6 和 Cd59a(-/-) 小鼠进行激光光凝诱导 CNV。激光照射后第 1、3、5 和 7 天处死每组动物。检查视网膜色素上皮-脉络膜-巩膜组织以确定CNV复合体的发生率和大小，并研究CD59a的半定量RT-PCR和Western blot分析。通过腹膜内注射重组可溶性小鼠 CD59a-IgG2a 融合蛋白 (rsCD59a-Fc)。或激光前 24 小时玻璃体内途径。我们的结果表明 CD59a（mRNA 和蛋白质）在激光诱导 CNV 过程中下调。 Cd59a(-/-)小鼠在疾病过程早期形成CNV复合体。在这些 Cd59a(-/-) 小鼠中也观察到 MAC 沉积增加。 rsCD59a-Fc 的施用通过阻断 MAC 形成来抑制小鼠模型中 CNV 复合物的发育，并且还抑制血管生成生长因子的表达。这些数据提供了强有力的证据，表明 CD59a 在调节补体激活和 MAC 形成中发挥着至关重要的作用，而 MAC 形成对于生长因子的释放至关重要，而生长因子可驱动小鼠激光诱导的 CNV 的发展。因此，我们的结果表明可溶性 CD59 抑制补体可能为当前治疗提供新的治疗替代方案。
We have shown that membrane attack complex (MAC) formation via the activation of the alternative pathway plays a central role in the laser-induced choroidal neovascularization (CNV). This study was undertaken to understand the role of a complement regulatory protein, CD59, which controls MAC assembly and function, in this model. CNV was induced by laser photocoagulation in C5713L/6 and Cd59a(-/-) mice using an argon laser. Animals from each group were sacrificed on day 1, 3, 5, and 7 postlaser. Retinal pigment epithelium-choroid-scleral tissue was examined to determine the incidence and size of CNV complex, and semi-quantitative RT-PCR and Western blot analysis for CD59a was studied. Recombinant soluble mouse CD59a-IgG2a fusion (rsCD59a-Fc) protein was injected via i.p. or intravitreal routes 24 h before laser. Our results demonstrated that CD59a (both mRNA and protein) was down-regulated during laser-induced CNV. Cd59a(-/-) mice developed CNV complex early in the disease process. Increased MAC deposition was also observed in these Cd59a(-/-) mice. Administration of rsCD59a-Fc inhibited the development of CNV complex in the mouse model by blocking MAC formation and also inhibited expression of angiogenic growth factors. These data provide strong evidence that CD59a plays a crucial role in regulating complement activation and MAC formation essential for the release of growth factors that drive the development of laser-induced CNV in mice. Thus, our results suggest that the inhibition of complement by soluble CD59 may provide a novel therapeutic alternative to current treatment.