Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration
Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration
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DOI：
10.1167/iovs.12-10849
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Matsubara, Joanne A.
中科院分区：
文献类型：
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作者：
Liu, Ruozhou Tom;Gao, Jiangyuan;Matsubara, Joanne A.
目的。玻璃疣是年龄相关性黄斑变性 (AMD) 的标志。淀粉样蛋白-β 1-40 (A beta 1-40) 是玻璃膜疣的一种成分，已知可刺激 RPE 中的炎症通路；然而，其体内作用尚不清楚。本研究的目的是在动物模型中检查 A beta 1-40 对与 AMD 相关的细胞因子表达和炎性体激活的影响。野生型大鼠接受玻璃体内注射 A beta 1-40，并在注射后第 1、4、14 和 49 天采集眼睛。通过 RT-PCR、免疫组织化学和悬浮阵列测定，分析 RPE、神经视网膜和玻璃体的细胞因子表达、炎症小体激活和小胶质细胞反应。通过细胞凋亡标记物和视网膜厚度评估视网膜细胞损失。 结果。 A beta 1-40 刺激 RPE/脉络膜和神经视网膜中 IL-6、TNF-α、IL-1 beta、IL-18、caspase-1、NLRP3 和 XAF1 基因的上调。在视网膜切片中发现IL-1β和IL-6免疫反应性增加，并且在注射Aβ的眼睛的玻璃体中发现IL-1β和IL-18水平升高。仅在注射后第 1 天，β 1-40 就诱导 CD11b/c 反应细胞适度增加。没有观察到促凋亡 XAF1 蛋白、p53、TUNEL 免疫反应性或视网膜变薄的证据。结论。这些结果证实了早期的体外研究，并支持玻璃膜疣成分 A beta 1-40 在 RPE 和视网膜中的促炎作用。炎症小体激活可能是体内这种效应的原因。该模型有助于理解炎症小体激活的细胞触发因素，并提出与 AMD 病因相关的外视网膜早期炎症事件。 （投资眼科可见科学。2013 年；54：2225-2237）DOI：10.1167/iovs.12-10849
PURPOSE. Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid-beta 1-40 (A beta 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE; however, its effect in vivo is not known. The purpose of this study was to examine the effect of A beta 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model.METHODS. Wild-type rats received intravitreal injections of A beta 1-40, and eyes were taken at days 1, 4, 14, and 49 postinjection. The RPE, neuroretina, and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry, and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness.RESULTS. A beta 1-40 stimulated upregulation of IL-6, TNF-alpha, IL-1 beta, IL-18, caspase-1, NLRP3, and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1 beta and IL-6 immunoreactivity was found in retinal sections, and elevated levels of IL-1 beta and IL-18 were found in the vitreous of A beta-injected eyes. A beta 1-40 induced a moderate increase in CD11b/c-reactive cells on day 1 postinjection only. No evidence of the proapoptotic XAF1 protein, p53, TUNEL immunoreactivity, or retinal thinning was observed.CONCLUSIONS. These results confirm earlier in vitro work and support the proinflammatory role of drusen component A beta 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful for understanding cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD. (Invest Ophthalmol Vis Sci. 2013;54:2225-2237) DOI: 10.1167/iovs.12-10849