Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy

Jang-Hyuk Yun^*

• Kangwon National University, Chuncheon, Republic of Korea

Retinal vascular leakage, resulting from increased endothelial permeability, is a major contributor to the pathogenesis of diabetic retinopathy (DR) and a key driver of visual impairment. This barrier dysfunction arises from both direct effects of proinflammatory cytokines on endothelial cells and indirect influences mediated by neighboring pericytes and microglia. In particular, pericyte loss and microglia-mediated inflammation exacerbate vascular dysfunction in DR. Given the known antiinflammatory and tissue-protective functions of interleukin-4 (IL-4), we investigated its potential role in modulating pericyte survival, microglial functional states, and endothelial permeability under diabetic conditions. IL-4 expression and downstream signaling pathways were significantly reduced in the retinas of streptozotocin-induced diabetic mice. Mechanistically, IL-4 enhanced pericyte survival by activating the phosphoinositide 3-kinase/protein kinase B pathway. IL-4 modulated microglial transcriptional and functional profiles via the activation of signal transducer and activator of transcription 6, promoting a microenvironment conducive to pericyte maintenance. In vitro, IL-4 restored endothelial barrier integrity and tight junction protein expression under high-glucose or tumor necrosis factor-alpha exposure by enhancing pericyte viability and promoting antiinflammatory microglial phenotypes. These findings suggest that IL-4 contributes to retinal vasculature stabilization in DR by preserving pericytes and modulating microglial responses, supporting its potential as a target for further preclinical investigation.