1Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
2Narayana Nethralaya Foundation, Bengaluru, India.
Commun Biol. 2019 Sep 20;2:348. doi: 10.1038/s42003-019-0588-y. eCollection 2019.
Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ- activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD.
年龄相关性黄斑变性（AMD）是一个全球性的问题，随着寿命的延长而不断扩大。虽然炎症显然导致 AMD 视力丧失，但机制仍存在争议。在这里，我们表明中性粒细胞在这个炎症过程中很重要。在早期 AMD 患者的视网膜和具有早期 AMD 样表型的小鼠模型中，我们都显示出中性粒细胞浸润。通过使用带状扫描共聚焦显微镜（RSCM）和 IFNλ 激活染料标记的正常中性粒细胞进行实验证实了这种浸润。缺乏脂钙蛋白-2（LCN-2）的中性粒细胞浸润大大减少。此外，早期 AMD 中增加的 IFNλ 水平触发中性粒细胞的激活和 LCN-2 的上调。LCN-2 通过调节整合素β1 水平来刺激激活的中性粒细胞的黏附和迁移，从而促进炎症。我们在小鼠模型中表明，抑制 AKT2 可中和 IFNλ 炎症信号，减少 LCN-2 介导的中性粒细胞浸润，并逆转早期 AMD 样表型变化。因此，AKT2 抑制剂可能在早期干性 AMD 中具有治疗潜力。
