Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice.

Abstract

Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T-cell-mediated inflammation is increasingly recognized as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and proinflammatory Th17 cells. It was hypothesized that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs and reduced the activation of microglia cells, the expression of proinflammatory factors including IL-17A, IL-6 and tumor necrosis factor, vascular leakage, vascular endothelial growth factor, and acellular capillaries, compared with diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.