Ghosh Sayan, Shang Peng, Yazdankhah Meysam, Bhutto Imran, Hose Stacey, Montezuma Sandra R, Luo Tianqi, Chattopadhyay Sreya, Qian Jiang, Lutty Gerard A, Ferrington Deborah A, Zigler J Samuel, Sinha Debasish
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Physiology, University of Calcutta, Kolkata, WB, India.
J Pathol. 2017 Apr;241(5):583-588. doi: 10.1002/path.4870. Epub 2017 Feb 20.
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 the 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 nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation 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 with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
年龄相关性黄斑变性（AMD）是一种复杂的进行性退行性眼病，会导致严重的中心视力丧失。最近的证据表明，免疫系统失调可能促使AMD的发生。我们推测，溶酶体介导的清除功能缺陷会导致视网膜色素上皮（RPE）中废物积聚，激活免疫系统并导致视网膜组织损伤和AMD。我们培育出了独特的基因工程小鼠，其中RPE细胞中的溶酶体介导清除（通过吞噬作用和自噬）受损，从而引发早期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，在我们的动物模型系统中，核因子-κB（NF-κB）和信号转导和转录激活因子1（STAT-1）可能作为一个复合体发挥作用，共同控制视网膜中LCN-2表达的上调并刺激炎症反应。这项研究显示，与年龄匹配的对照组相比，早期AMD患者脉络膜和视网膜中LCN-2阳性中性粒细胞的浸润增加。我们的结果表明，在我们的动物模型和人类AMD中，AKT2-NF-κB-LCN-2信号轴均参与激活炎症反应，使该途径成为AMD治疗的潜在靶点。版权所有©2016英国及爱尔兰病理学会。由约翰·威利父子有限公司出版。
