Diabetic retinopathy is a prevailing diabetes complication, and one of the leading causes of blindness worldwide. IL-17A is a cytokine involved in the onset of diabetic complications. In the current study, we examined the role of IL-17A in the development of retinal inflammation and long-term vascular pathology in diabetic mice. We found IL-17A expressing T cells and neutrophils in the retinal vasculature. Further, the IL-17A receptor was expressed on Muller glia, retinal endothelial cells, and photoreceptors. Finally, diabetes-mediated retinal inflammation, oxidative stress, and vascular leakage were all significantly lower in IL-17A^-/- mice. These are all clinically meaningful abnormalities that characterize the onset of diabetic retinopathy.

Purpose

Diabetes leads to progressive complications such as diabetic retinopathy, which is the leading cause of blindness within the working-age population worldwide. Interleukin (IL)-17A is a cytokine that promotes and progresses diabetes. The objective of this study was to determine the role of IL-17A in retinal capillary degeneration, and to identify the mechanism that induces retinal endothelial cell death. These are clinically meaningful abnormalities that characterize early-stage non-proliferative diabetic retinopathy.

Methods

Retinal capillary degeneration was examined in vivo using the streptozotocin (STZ) diabetes murine model. Diabetic-hyperglycemia was sustained for an 8-month period in wild type (C57BL/6) and IL-17A^-/- mice to elucidate the role of IL-17A in retinal capillary degeneration. Further, ex vivo studies were performed in retinal endothelial cells to identify the IL-17A-dependent mechanism that induces cell death.

Results

It was determined that diabetes-induced retinal capillary degeneration was significantly lower in IL-17A^-/- mice. Further, retinal endothelial cell death occurred through an IL-17A/IL-17R ➔ Act1/FADD signaling cascade, which caused caspase-mediated apoptosis.

Conclusion

These are the first findings that establish a pathologic role for IL-17A in retinal capillary degeneration. Further, a novel IL-17A-dependent apoptotic mechanism was discovered, which identifies potential therapeutic targets for the early onset of diabetic retinopathy.