Research Program for Experimental Ophthalmology, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University, Muellner Hauptstrasse 48, 5020, Salzburg, Austria.
Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria.
Sci Rep. 2020 Oct 19;10(1):17659. doi: 10.1038/s41598-020-74755-w.
The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. Impaired autophagy and continuous cellular stress are associated with various disorders, such as dry age-related macular degeneration (AMD), a disease for which effective therapies are lacking. Cysteinyl leukotriene receptor (CysLTR) 1 is a potential modulator of autophagy; thus, the aim of this study was to investigate the role of CysLTR1 in autophagy regulation in the RPE cell line ARPE-19. The polarized ARPE-19 monolayer exhibited expression of CysLTR1, which was colocalized with β-tubulin III. In ARPE-19 cells, autophagic activity was rhythmically regulated and was increased upon CysLTR1 inhibition by Zafirlukast (ZK) treatment. HO affected the proautophagic regulatory effect of ZK treatment depending on whether it was applied simultaneously with or prior to ZK treatment. Furthermore, mRNA levels of genes related to the leukotriene system, autophagy and the unfolded protein response were positively correlated. As CysLTR1 is involved in autophagy regulation under basal and oxidative stress conditions, a dysfunctional leukotriene system could negatively affect RPE functions. Therefore, CysLTR1 is a potential target for new treatment approaches for neurodegenerative disorders, such as AMD.
视网膜色素上皮（RPE）是体内暴露于最高水平吞噬作用和氧化应激的组织之一，依赖于自噬功能。自噬功能受损和持续的细胞应激与各种疾病有关，例如干性年龄相关性黄斑变性（AMD），这种疾病缺乏有效的治疗方法。半胱氨酰白三烯受体（CysLTR）1 是自噬的潜在调节剂；因此，本研究旨在探讨 CysLTR1 在 RPE 细胞系 ARPE-19 中自噬调节中的作用。极化的 ARPE-19 单层表达 CysLTR1，其与 β-微管蛋白 III 共定位。在 ARPE-19 细胞中，自噬活性呈节律性调节，CysLTR1 抑制剂 Zafirlukast（ZK）处理可增加自噬活性。HO 的应用是否与 ZK 处理同时或之前影响 ZK 处理的促自噬调节作用。此外，与白三烯系统、自噬和未折叠蛋白反应相关的基因的 mRNA 水平呈正相关。由于 CysLTR1 参与基础和氧化应激条件下的自噬调节，因此功能失调的白三烯系统可能会对 RPE 功能产生负面影响。因此，CysLTR1 是治疗 AMD 等神经退行性疾病的新治疗方法的潜在靶点。
