Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.
Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.
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DOI：
10.1002/path.4870
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Sinha D
中科院分区：
文献类型：
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作者：
Ghosh S;Shang P;Yazdankhah M;Bhutto I;Hose S;Montezuma SR;Luo T;Chattopadhyay S;Qian J;Lutty GA;Ferrington DA;Zigler JS Jr;Sinha D
视网膜相关性黄斑变性（AMD）是一种复杂的进行性退行性眼病，导致严重的中心视力丧失。最近的证据表明，免疫系统失调可能有助于AMD的发展。我们假设缺陷的溶酶体介导的清除导致废物在视网膜色素上皮（RPE）中积累，激活免疫系统并导致视网膜组织损伤和AMD。我们已经产生了独特的基因工程小鼠，其中RPE细胞中溶酶体介导的清除（通过吞噬作用和自噬作用）受到损害，导致早期AMD特征的发展。我们最近的数据表明，脂质运载蛋白-2（LCN-2）与该小鼠模型中诱导的炎症反应之间存在联系。我们发现NFκB和STAT-1在我们的动物模型系统中可能作为一个复合物发挥作用，共同控制视网膜中LCN-2表达的上调并刺激炎症反应。该研究揭示了与年龄匹配的对照相比，早期AMD患者的脉络膜和视网膜中LCN-2阳性中性粒细胞的浸润增加。我们的研究结果表明，在我们的动物模型和人AMD中，AKT 2/NFκB/LCN-2信号传导轴参与激活炎症反应，使该途径成为AMD治疗的潜在靶点。
Age–related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing development of features of early AMD. Our recent data indicate a link between Lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that NFκB and STAT-1 may function as a complex in our animal model system, together controlling the up-regulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2 positive neutrophils in the choroid and retina of early AMD patients as compared to age-matched controls. Our results demonstrate that both in our animal model and in human AMD the AKT2/NFκB/LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment.