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 recognised 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 pro-inflammatory Th17 cells. We hypothesised 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 pro-inflammatory factors including interleukin-17A, interleukin-6 and tumour necrosis factor, vascular leakage, vascular endothelial growth factor and acellular capillaries, compared to 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.