Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China.
Laboratory of Molecular ophthalmology, Tianjin Medical University, Tianjin, China.
FASEB J. 2021 Nov;35(11):e22008. doi: 10.1096/fj.202100807RR.
An impaired blood-retinal barrier (BRB) leads to diabetic macular edema (DME), which is a major complication of Diabetic retinopathy (DR). Mediators such as inflammation cause BRB breakdown. However, the explicit mechanism of its disruption is largely unknown. In this study, we identified tumor necrosis factor ligand-related molecule 1A (TL1A) as a crucial factor which protect retinal endothelial cells integrity in DR. By providing both human and mouse data, we show that TL1A is significantly decreased in the retinas of DME patients and diabetic rodents. We further demonstrate that the loss of TL1A accelerated diabetes-induced retinal barrier breakdown. TL1A supplementation protects the diabetic retina against BRB breakdown. Mechanistically, TL1A stabilize intracellular junctions and protect vascular integrity by blocking SHP1-Src-regulated VE-cadherin phosphorylation. Collectively, our findings reveal that loss of TL1A in the retina leads to increased vascular permeability in DR, and that TL1A treatment is of potential therapeutic interest for the treatment of DME.
受损的血视网膜屏障 (BRB) 可导致糖尿病性黄斑水肿 (DME)，这是糖尿病性视网膜病变 (DR) 的主要并发症。炎症等介质可导致 BRB 破裂。然而，其破坏的确切机制在很大程度上尚不清楚。在这项研究中，我们发现肿瘤坏死因子配体相关分子 1A (TL1A) 是保护 DR 中视网膜内皮细胞完整性的关键因素。通过提供人和小鼠的数据，我们表明 TL1A 在 DME 患者和糖尿病啮齿动物的视网膜中显著减少。我们进一步证明，TL1A 的缺失加速了糖尿病诱导的视网膜屏障破裂。TL1A 补充可保护糖尿病视网膜免受 BRB 破裂。在机制上，TL1A 通过阻断 SHP1-Src 调节的 VE-钙粘蛋白磷酸化来稳定细胞内连接并保护血管完整性。总之，我们的研究结果表明，视网膜中 TL1A 的缺失可导致 DR 中血管通透性增加，TL1A 治疗可能具有治疗 DME 的潜力。
