Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany; University of Namur, Faculty of Medicine, Biomedical Sciences Department, 61 -5000, Namur, Belgium.
Biochem Biophys Res Commun. 2020 Jul 23;528(2):261-268. doi: 10.1016/j.bbrc.2020.05.114. Epub 2020 May 29.
Degeneration of the retinal pigment epithelium (RPE) is a hallmark of atrophic age-related macular degeneration (AMD). Microglia mediated inflammatory responses and oxidative stress are critical pathophysiological processes in the onset and progression of RPE degeneration. Given the central role of the RPE, strategies to protect these cells from damage caused by oxidative stress and inflammation present a promising therapeutic approach to mitigate AMD. Ligands for the translocator protein (18 kDa) (TSPO) have been shown to confer protection against retinal inflammatory responses and neurodegeneration by acting primarily through retinal glia. However, despite RPE cells demonstrating strong TSPO expression, it remains unclear whether TSPO ligands could also inhibit inflammatory responses of RPE cells. Here, we investigated the influence of three different TSPO ligands XBD173, PK11195 and Ro5-4864 on inflammatory responses in human ARPE-19 cells triggered by supernatants from reactive human microglial cells and the lysosomal destabilizer, LLOMe. Our findings revealed that TSPO ligands significantly inhibited proinflammatory gene expression, inflammasome-mediated caspase-1 activation, lipid accumulation and intracellular ROS levels in stressed ARPE-19 cells. Notably, TSPO ligands induced activation of Nrf2 pathway and its downstream regulated genes in ARPE-19 cells, with Hmox-1 being the most strongly upregulated gene. Collectively, our study indicates that TSPO ligands can enhance the Nrf2 antioxidant pathway in RPE cells and protect them from cellular damage resulting from inflammation and oxidative stress.
视网膜色素上皮 (RPE) 的退化是萎缩性年龄相关性黄斑变性 (AMD) 的标志。小胶质细胞介导的炎症反应和氧化应激是 RPE 退化发生和进展的关键病理生理过程。鉴于 RPE 的核心作用，保护这些细胞免受氧化应激和炎症损伤的策略为减轻 AMD 提供了一种很有前途的治疗方法。转位蛋白 (18 kDa) (TSPO) 的配体已被证明通过主要作用于视网膜胶质细胞来对抗视网膜炎症反应和神经退行性变提供保护。然而，尽管 RPE 细胞表现出强烈的 TSPO 表达，但尚不清楚 TSPO 配体是否也可以抑制 RPE 细胞的炎症反应。在这里，我们研究了三种不同的 TSPO 配体 XBD173、PK11195 和 Ro5-4864 对由反应性人小胶质细胞上清液和溶酶体稳定剂 LLOMe 触发的人 ARPE-19 细胞炎症反应的影响。我们的发现表明，TSPO 配体可显著抑制应激 ARPE-19 细胞中促炎基因表达、炎性体介导致 caspase-1 激活、脂质积累和细胞内 ROS 水平。值得注意的是，TSPO 配体诱导 ARPE-19 细胞中 Nrf2 通路及其下游调节基因的激活，其中 Hmox-1 是上调最明显的基因。总的来说，我们的研究表明，TSPO 配体可以增强 RPE 细胞中的 Nrf2 抗氧化途径，并保护它们免受炎症和氧化应激引起的细胞损伤。
