Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast 97 Lisburn Road, Belfast BT9 7BL, UK.
Department of Medicine, Division of Endocrinology, Diabetes & Metabolic Diseases, Medical University of South Carolina, Charleston, SC 29452, USA.
Int J Mol Sci. 2021 Nov 2;22(21):11876. doi: 10.3390/ijms222111876.
We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.
我们之前曾报道过，抑制 Janus 激酶 1（JAK1）信号可改善白细胞介素 17A（IL-17A）介导的血视网膜屏障（BRB）功能障碍。患有糖尿病视网膜病变（DR）的患者，尤其是患有糖尿病黄斑水肿的患者，其血液和眼内液中 IL-17A 水平更高。本研究旨在了解 JAK1 抑制是否可以预防 2 型糖尿病（T2D）模型 db/db 小鼠的 BRB 功能障碍。一项体外研究表明，高葡萄糖处理破坏了 bEnd3 细胞中 Claudin-5 和 ARPE19 细胞中 ZO-1 的连接分布，而托法替尼柠檬酸盐处理可防止高葡萄糖介导的紧密连接破坏。在三个月大的 db/db 小鼠中观察到白蛋白渗漏，同时 JAK1 的磷酸化形式（pJAK1）水平升高。用托法替尼柠檬酸盐治疗两个半月大的 db/db 小鼠两周可显著减少视网膜白蛋白渗漏并降低 pJAK1 表达。在人 DR 视网膜中也检测到 pJAK1 表达。我们的研究结果表明，JAK1 抑制可改善 T2D 中的 BRB 功能障碍，托法替尼柠檬酸盐等 JAK1 抑制剂可能被重新用于治疗糖尿病黄斑水肿。
