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Abstract：
Blood-retinal barrier (BRB) dysfunction underlies macular oedema in many sight-threatening conditions, including diabetic macular oedema, neovascular age-related macular degeneration and uveoretinitis. Inflammation plays an important role in BRB dysfunction. This study aimed to understand the role of the inflammatory cytokine IL-17A in BRB dysfunction and the mechanism involved. Human retinal pigment epithelial (RPE) cell line ARPE19 and murine brain endothelial line bEnd.3 were cultured on transwell membranes to model the outer BRB and inner BRB, respectively. IL-17A treatment (3 days in bEnd.3 cells and 6 days in ARPE19 cells) disrupted the distribution of claudin-5 in bEnd.3 cells and ZO-1 in ARPE19 cells, reduced the transepithelial/transendothelial electrical resistance (TEER) and increased permeability to FITC-tracers in vitro. Intravitreal (20 ng/1 μL/eye) or intravenous (20 ng/g) injection of recombinant IL-17A induced retinal albumin leakage within 48 h in C57BL/6J mice. Mechanistically, IL-17A induced Janus kinase 1 (JAK1) phosphorylation in bEnd.3 but not ARPE19 cells. Blocking JAK1 with Tofacitinib prevented IL-17A-mediated claudin-5 dysmorphia in bEnd.3 cells and reduced albumin leakage in IL-17A-treated mice. Our results suggest that IL-17A can damage the BRB through the activating the JAK1 signaling pathway, and targeting this pathway may be a novel approach to treat inflammation-induced macular oedema.
摘要：
血-视网膜屏障（BRB）功能障碍是许多视力威胁的黄斑水肿的基础，包括糖尿病性黄斑水肿,新生血管性年龄相关性黄斑变性和葡萄膜视网膜炎。炎症在BRB功能障碍中起重要作用。本研究旨在了解炎性细胞因子IL-17A在BRB功能障碍中的作用及其机制。在transwell膜上培养人视网膜色素上皮(RPE)细胞系ARPE19和小鼠脑内皮细胞系bEnd.3，以模拟外部BRB和内部BRB，分别。IL-17A处理（在bEnd.3细胞中3天，在ARPE19细胞中6天）破坏了claudin-5在bEnd.3细胞和ZO-1在ARPE19细胞中的分布，在体外降低跨上皮/跨内皮电阻（TEER）并增加对FITC示踪剂的通透性。在C57BL/6J小鼠中，玻璃体内（20ng/1μL/眼）或静脉内（20ng/g）注射重组IL-17A在48小时内诱导视网膜白蛋白渗漏。机械上,IL-17A在bEnd.3而不是ARPE19细胞中诱导Janus激酶1(JAK1)磷酸化。用Tofacitinib阻断JAK1可防止bEnd.3细胞中IL-17A介导的claudin-5畸形，并减少IL-17A治疗小鼠的白蛋白泄漏。我们的结果表明，IL-17A可以通过激活JAK1信号通路来损伤BRB，靶向该途径可能是治疗炎症诱导的黄斑水肿的新方法。
