The Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA.
J Immunol Res. 2021 Jun 18;2021:9975628. doi: 10.1155/2021/9975628. eCollection 2021.
Age-related macular degeneration (AMD), a degenerative disease of the outer retina, is the leading cause of blindness among the elderly. A hallmark of geographic atrophy (GA), an advanced type of nonneovascular AMD (dry AMD), is photoreceptor and retinal pigment epithelium (RPE) cell death. Currently, there are no FDA-approved therapies for GA due to a lack of understanding of the disease-causing mechanisms. Increasing evidence suggests that chronic inflammation plays a predominant role in the pathogenesis of dry AMD. Dead or stressed cells release danger signals and inflammatory factors, which causes further damage to neighboring cells. It has been reported that type I interferon (IFN) response is activated in RPE cells in patients with AMD. However, how RPE cells sense stress to initiate IFN response and cause further damage to the retina are still unknown. Although it has been reported that RPE can respond to extracellularly added dsRNA, it is unknown whether and how RPE detects and senses internally generated or internalized nucleic acids. Here, we elucidated the molecular mechanism by which RPE cells sense intracellular nucleic acids. Our data demonstrate that RPE cells can respond to intracellular RNA and induce type I IFN responses via the RIG-I (DExD/H-box helicase 58, DDX58) RNA helicase. In contrast, we showed that RPE cells were unable to directly sense and respond to DNA through the cGAS-STING pathway. We demonstrated that this was due to the absence of the cyclic GMP-AMP synthase (cGAS) DNA sensor in these cells. The activation of IFN response via RIG-I induced expression of cell death effectors and caused barrier function loss in RPE cells. These data suggested that RPE-intrinsic pathways of nucleic acid sensing are biased toward RNA sensing.
年龄相关性黄斑变性（AMD）是一种外视网膜退行性疾病，是老年人致盲的主要原因。地理萎缩（GA）是一种无血管新生的 AMD（干性 AMD）的晚期类型，其特征是光感受器和视网膜色素上皮（RPE）细胞死亡。由于对致病机制缺乏了解，目前还没有 FDA 批准的 GA 治疗方法。越来越多的证据表明，慢性炎症在干性 AMD 的发病机制中起主要作用。死亡或应激细胞释放危险信号和炎症因子，导致邻近细胞进一步受损。据报道，AMD 患者的 RPE 细胞中激活了 I 型干扰素（IFN）反应。然而，RPE 细胞如何感知应激以启动 IFN 反应并对视网膜造成进一步损伤仍不清楚。尽管已经报道 RPE 可以对外源性添加的 dsRNA 做出反应，但尚不清楚 RPE 是否以及如何检测和感知内源性或内化的核酸。在这里，我们阐明了 RPE 细胞感知细胞内核酸的分子机制。我们的数据表明，RPE 细胞可以通过 RIG-I（DExD/H 盒解旋酶 58，DDX58）RNA 解旋酶对细胞内 RNA 做出反应并诱导 I 型 IFN 反应。相比之下，我们表明 RPE 细胞无法通过 cGAS-STING 途径直接感知和响应 DNA。我们表明，这是由于这些细胞中缺乏环鸟苷酸-腺苷酸合酶（cGAS）DNA 传感器。通过 RIG-I 激活 IFN 反应诱导细胞死亡效应物的表达，并导致 RPE 细胞的屏障功能丧失。这些数据表明，RPE 细胞中核酸感应的固有途径偏向于 RNA 感应。
