Cruz-Guilloty Fernando, Saeed Ali M, Echegaray Jose J, Duffort Stephanie, Ballmick Asha, Tan Yaohong, Betancourt Michel, Viteri Eduardo, Ramkhellawan Ghansham C, Ewald Eric, Feuer William, Huang Deqiang, Wen Rong, Hong Li, Wang Hua, Laird James M, Sene Abdoulaye, Apte Rajendra S, Salomon Robert G, Hollyfield Joe G, Perez Victor L
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA ; Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Int J Inflam. 2013;2013:503725. doi: 10.1155/2013/503725. Epub 2013 Mar 7.
Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.
年龄相关性黄斑变性（AMD）是发达国家失明的主要原因。氧化应激和炎症与AMD有关，但确切机制仍不清楚。羧乙基吡咯（CEP）是一种与AMD相关的脂质过氧化产物。我们之前证明，用CEP修饰的白蛋白免疫的小鼠在外视网膜出现了类似AMD的退行性变化。在此，我们研究了免疫小鼠病变发展的动力学以及视网膜色素上皮和光感受器外段之间的光感受器间基质（IPM）内巨噬细胞的存在情况。我们观察到，在明显病变出现之前，与年轻的年龄匹配对照相比，免疫小鼠体内巨噬细胞数量显著且呈时间依赖性增加。这些变化在BALB/c小鼠中比在C57BL/6小鼠中更明显。重要的是，浸润IPM的巨噬细胞向M1表型极化，但仅在免疫小鼠中如此。此外，当对Ccr2缺陷小鼠进行免疫时，IPM中不存在巨噬细胞，也未观察到视网膜病变，这表明在我们的模型中这些细胞具有有害作用。这项工作提供了将针对氧化损伤的免疫反应与未来AMD部位促炎巨噬细胞的存在联系起来的机制证据，并通过实验证明操纵免疫可能是调节AMD发展的一个靶点。
