The IL-6 Induced Retinal Iron Sequestration Response

项目总结 铁在健康和患病的视网膜中都起着至关重要的作用。的长期目标 拟议的研究是为了了解炎症与视网膜疾病之间的关系 促进铁的失调，并发现如何防止视网膜铁中毒。铁是 在视网膜中是线粒体能量产生、膜合成和 视觉周期，但当调控不当时，就会成为氧化应激的中心生产者。 铁的毒性在视网膜疾病中很明显：1)铁导致视网膜快速退化 眼内异物进入眼内后进入眼睛。2)人类AMD视网膜有 与年龄匹配的对照组相比，铁含量更高，这表明铁超载可能在AMD中起作用 发病机制。3)与这一假设一致，在遗传性疾病无浆蛋白血症中， 铜蓝蛋白铁氧合酶(CP)的缺失会导致视网膜铁蓄积和早期发病 黄斑变性。4)CP及其同系物Hephestn基因敲除的小鼠有 年龄相关的视网膜铁超载和退行性改变是AMD的共同特征，包括 补体激活和视网膜下新生血管(导致湿性AMD)。近期 来自非眼部细胞的证据表明，白细胞介素6(IL-6)可以触发一种“细胞铁” 隔离反应“，以防止微生物获取它们生长所需的铁和 复制。这与眼内和血清中IL-6水平升高有关 提示IL-6可能促进了AMD视网膜铁超载。建议进行的实验 本文将利用人类IPSC-RPE细胞培养、小鼠模型和死后人类组织 以明确IL-6视网膜铁隔离反应。一种IL-6转导信号的抑制剂 将对路径进行测试。在激活或抑制IL-6通路后，水平的变化 将对铁及其转运体进行评估。这些变化将与 AMD与正常尸检视网膜的对比。预计这些研究将导致 减少炎症诱导的铁的抗AMD新方法的开发 积累。

PROJECT SUMMARY Iron plays a critical role in both the healthy and diseased retina. The long term goals of the proposed studies are to understand how inflammation associated with retinal disease promotes iron dysregulation, and discover how to protect against retinal iron toxicity. Iron is necessary in the retina for mitochondrial energy production, membrane synthesis and the visual cycle, but becomes a central producer of oxidative stress when improperly regulated. Iron toxicity is evident in retinal disease as follows: 1) Iron causes rapid retinal degeneration following entry into the eye carried by an intraocular foreign body. 2) Human AMD retinas have more iron than age-matched controls, suggesting that iron overload may play a role in AMD pathogenesis. 3) Consistent with this hypothesis, in the inherited disease aceruloplasminemia, loss of the ferroxidase ceruloplasmin (Cp) results in retinal iron accumulation and early onset macular degeneration. 4) Mice with knockout for Cp and its homolog hephaestin (Heph) have an age-dependent retinal iron overload and degeneration sharing features of AMD, including complement activation and subretinal neovascularization (which causes wet AMD). Recent evidence from non-ocular cells indicates that interleukin 6 (IL-6) can trigger a “cellular iron sequestration response” to prevent microbes from accessing the iron they need for growth and replication. This, combined with the finding of elevated intraocular and serum IL-6 levels in AMD, suggest that IL-6 may promote retinal iron overload in AMD. Experiments proposed herein will utilize human iPSC-RPE cell culture, mouse models, and post mortem human tissue to define the IL-6 retinal iron sequestration response. An inhibitor of the IL-6 trans-signaling pathway will be tested. Following activation or inhibition of IL-6 pathways, changes in the levels of iron and its transporters will be assessed. These changes will be correlated with those in AMD versus normal post mortem retinas. It is expected that these studies will lead to development of novel anti-AMD approaches that diminish inflammation-induced iron accumulation.