Complement Regulatory Protein CD46 Protects against Choroidal Neovascularization in Mice
Complement Regulatory Protein CD46 Protects against Choroidal Neovascularization in Mice
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DOI：
10.1016/j.ajpath.2014.06.001
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发表时间：
2014-09-01
影响因子：
6
通讯作者：
Bora, Nalini S.
中科院分区：
文献类型：
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作者：
Lyzogubov, Valeriy;Wu, Xiaobo;Bora, Nalini S.
人们越来越认识到补体系统失调是导致年龄相关性黄斑变性的一个因素。尽管补体调节剂 CD46 在人类中普遍表达，但在小鼠中，以前认为它仅在精子中表达。我们在野生型 (WT) C57BL/6J 小鼠的眼后段（神经元视网膜、视网膜色素上皮和脉络膜）中检测到 CD46 mRNA 和蛋白。 Cd46(-/-)敲除小鼠的视网膜和脉络膜中的膜攻击复合物和血管内皮生长因子(VEGF)水平增加。 Cd46(-/-)小鼠也更容易受到激光诱导的脉络膜新生血管(CNV)的影响。在Cd46(-/-)小鼠中，治疗后第2天，19%的激光点呈CNV阳性，但在WT小鼠中未检测到阳性点。第3天，Cd46(-/-)小鼠中42%的激光斑点呈阳性，但WT小鼠中只有11%。第 7 天时，Cd46(-/-) 和 WT 小鼠中均观察到完全发育的 CNV 复合体；然而，Cd46(-/-) 小鼠的病变大小显着增加（P < 0.05）。我们的研究结果为小鼠眼中 CD46 的表达以及 CD46 在防止激光诱导的 CNV 中的作用提供了证据。我们认为Cd46(-/-)小鼠由于补体抑制不足而对实验性CNV具有更大的敏感性，从而导致膜攻击复合物沉积和VEGF表达增加。
Dysregulation of the complement system is increasingly recognized as a contributing factor in age-related macular degeneration. Although the complement regulator CD46 is expressed ubiquitously in humans, in mouse it was previously thought to be expressed only on spermatozoa. We detected CD46 mRNA and protein in the posterior ocular segment (neuronal retina, retinal pigment epithelium, and choroid) of wild-type (WT) C57BL/6J mice. Cd46(-/-) knockout mice exhibited increased levels of the membrane attack complex and of vascular endothelial growth factor (VEGF) in the retina and choroid. The Cd46(-/-) mice were also more susceptible to laser-induced choroidal neovascularization (CNV). In Cd46(-/-) mice, 19% of laser spots were positive for CNV at day 2 after treatment, but no positive spots were detected in WT mice. At day 3, 42% of laser spots were positive in Cd46(-/-) mice, but only 11% in WT mice. A fully developed CNV complex was noted in both Cd46(-/-) and WT mice at day 7; however, lesion size was significantly (P < 0.05) increased in Cd46(-/-) mice. Our findings provide evidence for expression of CD46 in the mouse eye and a role for CD46 in protection against laser-induced CNV. We propose that the Cd46(-/-) mouse has a greater susceptibility to experimental CNV because of insufficient complement inhibition, which leads to increased membrane attack complex deposition and VEGF expression.