Tumor necrosis factor ligand-related molecule 1A maintains blood-retinal barrier via modulating SHP-1-Src-VE-cadherin signaling in diabetic retinopathy

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.