Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis
Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis
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DOI：
10.1073/pnas.0608167104
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发表时间：
2007-02-13
影响因子：
11.1
通讯作者：
Miller, Joan W.
中科院分区：
文献类型：
--
作者：
Nakazawa, Toru;Hisatomi, Toshio;Miller, Joan W.
光感受器凋亡是视网膜脱离（RD）和其他几种视觉障碍中视力丧失的主要原因，但其潜在机制仍然难以捉摸。最近，据报道，RD 和糖尿病视网膜病变患者的玻璃体液样本以及神经退行性疾病（包括阿尔茨海默病和多发性硬化症）患者的脑组织中单核细胞趋化蛋白 1 (MCP-1) 的表达增加。在此，我们报道 MCP-1 在 RD 实验模型中介导光感受器凋亡中发挥关键作用。 RD 导致 Muller 胶质细胞中 MCP-1 表达增加，以及脱离视网膜中 CD11b(+) 巨噬细胞/小胶质细胞增加。 MCPA 阻断抗体大大减少了巨噬细胞/小胶质细胞浸润和 RD 诱导的光感受器细胞凋亡。证实了这些结果，MCP-1基因缺陷小鼠在RD后表现出巨噬细胞/小胶质细胞浸润显着减少，并且光感受器细胞凋亡非常少。在原代视网膜混合培养物中，MCP-1 对恢复素 (+) 光感受器具有细胞毒性，并且通过免疫耗竭培养物中的巨噬细胞/小胶质细胞来消除这种毒性。在体内，编码 CD11b/CD18 的基因的缺失几乎消除了 RD 后巨噬细胞/小胶质细胞对视网膜的浸润和光感受器的丧失。因此，MCP-1 表达以及随后的巨噬细胞/小胶质细胞浸润和激活对于 RD 诱导的光感受器凋亡至关重要。该通路可能是预防 RD 和其他具有共同病因的 CNS 疾病中光感受器凋亡的重要治疗靶点。
Photoreceptor apoptosis is a major cause of visual loss in retinal detachment (RD) and several other visual disorders, but the underlying mechanisms remain elusive. Recently, increased expression of monocyte chemoattractant protein 1 (MCP-1) was reported in vitreous humor samples of patients with RD and diabetic retinopathy as well as in the brain tissues of patients with neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis. Here we report that MCP-1 plays a critical role in mediating photoreceptor apoptosis in an experimental model of RD. RD led to increased MCP-1 expression in the Muller glia and increased CD11b(+) macrophage/microglia in the detached retina. An MCPA blocking antibody greatly reduced macrophage/microglia infiltration and RD-induced photoreceptor apoptosis. Confirming these results, MCP-1 gene-deficient mice showed significantly reduced macrophage/microglia infiltration after RD and very little photoreceptor apoptosis. In primary retinal mixed cultures, MCP-1 was cytotoxic for recoverin(+) photoreceptors, and this toxicity was eliminated through immunodepleting macrophage/microglia from the culture. In vivo, deletion of the gene encoding CD11b/CD18 nearly eliminated macrophage/microglia infiltration to the retina after RD and the loss of photoreceptors. Thus, MCP-1 expression and subsequent macrophage/microglia infiltration and activation are critical for RD-induced photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in RD and other CNS diseases that share a common etiology.