Role of complement receptors and microglia in age-related macular degeneration

补体受体和小胶质细胞在年龄相关性黄斑变性中的作用

• 批准号: 268718306
• 负责人: Professor Dr. Thomas Langmann
• 金额: --
• 依托单位: Zentrum für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268718306?language=en
• 关键词: Role; complement; receptors; microglia; age

Age-related macular degeneration (AMD) is a leading cause of blindness in industrialized countries. Early AMD manifests as drusen deposits between the outer retina and the pigment epithelium. AMD can progress to late stage forms including choroidal neovascularization (CNV) and an atrophic form with macular degeneration of photoreceptors and the pigment epithelium. The etiology of AMD is not completely understood. However, genetic association studies in large patient cohorts and in situ analyses in AMD eyes as well as animal models mimicking some features of AMD have identified an important contribution of dysregulated innate immunity in the eye. Our project of the first funding period of FOR2240 has revealed local dysregulation of complement factors in ocular fluids of AMD patients and found a correlation of disease progression with hyperreflective foci (HF) as potential imaging markers for retinal immune cells. Furthermore, using a light damage paradigm and laser-triggered CNV in mice we established a comprehensive analysis of microglia and macrophages in the retina. Resident microglia-specific targeting of key immune pathways and immunomodulatory compounds could elucidate a vicious cycle of microglia reactivity, retinal degeneration and neoangiogenesis. These findings together provide evidence for an interaction of reactive microglia with aberrant complement proteins in the pathogenesis of AMD. However, the underlying mechanisms that link both systems are only incompletely explored. In this follow-up project we postulate that particularly the anaphylatoxin complement cleavage products C3a and C5a sustain chronic microglia reactivity via receptor-mediated recruitment and activation. We further postulate that hyperreflective foci could potentially mirror complement-regulated microglia responses and may therefore be used to monitor disease development in AMD patients and animal models. The project is subdivided into four specific aims in which we will determined the impact of C3a/C5a anaphylatoxins on microglia in vitro, test the effects of microglial C3a/C5a receptor deficiency in the laser-CNV and light damage models, evaluate the expression and localization of C3aR/C5aR in human retinal sections, and finally correlate the dynamics of hyperreflective foci with ocular complement factors in AMD patients and controls. The results of these studies will provide new insights into the immune-related etiology of AMD and may foster the development of novel effective treatments.

视网膜相关性黄斑变性（AMD）是工业化国家致盲的主要原因。早期AMD表现为外视网膜和色素上皮之间的玻璃疣沉积物。AMD可发展为晚期形式，包括脉络膜新生血管形成（CNV）和具有光感受器和色素上皮的黄斑变性的萎缩形式。AMD的病因尚未完全了解。然而，在大型患者队列中的遗传关联研究和AMD眼睛中的原位分析以及模拟AMD的一些特征的动物模型已经确定了眼睛中先天免疫失调的重要贡献。我们的项目的第一个资助期的FOR 2240已揭示了局部失调的补体因子在眼液AMD患者，并发现了相关的疾病进展与高反射灶（HF）作为潜在的成像标记物的视网膜免疫细胞。此外，使用小鼠中的光损伤范例和激光触发的CNV，我们建立了视网膜中小胶质细胞和巨噬细胞的综合分析。常驻小胶质细胞特异性靶向的关键免疫途径和免疫调节化合物可以阐明小胶质细胞反应性，视网膜变性和新生血管的恶性循环。这些发现共同为反应性小胶质细胞与异常补体蛋白在AMD发病机制中的相互作用提供了证据。然而，连接这两个系统的基本机制只是不完全探索。在这个后续项目中，我们假设，特别是过敏毒素补体裂解产物C3 a和C5 a通过受体介导的募集和激活维持慢性小胶质细胞反应性。我们进一步假设，高反射灶可能反映补体调节的小胶质细胞反应，因此可用于监测AMD患者和动物模型的疾病发展。该项目被细分为四个具体目标，其中我们将确定C3 a/C5 a过敏毒素对小胶质细胞的影响，在激光CNV和光损伤模型中测试小胶质细胞C3 a/C5 a受体缺陷的影响，评估C3 aR/C5 aR在人视网膜切片中的表达和定位，最后将AMD患者和对照组中的高反射灶的动力学与眼部补体因子相关联。这些研究的结果将为AMD的免疫相关病因学提供新的见解，并可能促进新的有效治疗方法的开发。