RORγ inhibition attenuates vasculopathy in mice and rats with diabetic retinopathy by reducing Th17 cells and increasing the functionality of Tregs

Abstract

Purpose : Purpose: The vision-threatening vascular pathology that can develop in diabetic retinopathy (DR) is highly influenced by angiogenic factors such as vascular endothelial growth factor (VEGF). There is evidence that retinal inflammation also promotes vascular injury in DR, but the mechanisms involved are not fully understood. We previously reported that increasing the number of anti-inflammatory Foxp3 regulatory T cells (Tregs) reduced inflammation and vasculopathy in mice with proliferative retinopathy. Tregs exist in balance with pro-inflammatory Th17 cells via the retinoic acid receptor-related orphan receptor (ROR)γ. Here, we hypothesised that RORγ inhibition would attenuate retinal inflammation and vasculopathy in DR by reducing the abundance of Th17 cells and increasing Treg functionality.

Methods : Methods: Female Sprague Dawley rats were made diabetic with streptozotocin (STZ) and then studied for 8 weeks. To evaluate Tregs, male Foxp3^rfp mice (C57Bl6/J background) expressing Foxp3 as a red fluorescent protein (rfp) were administered STZ and studied for 26 weeks. Comparisons were made to non-diabetic controls, and animals administered the RORγ inhibitor, SR2211 (3mg/kg) intraperitoneally one week after STZ and once every three days until the end of the studies. Twenty-four to 36 animals were studied per group, and data were analysed by unpaired t-tests or one-way ANOVAs. Statistical significance was defined as p<0.05.

Results : Results: SR2211 had no effect on body weight and blood glucose and Hba1c levels. In rats with DR, the number of Th17 cells was increased compared to non-diabetic rats and reduced with SR2211. In mice with DR, SR2211 did not alter the number of Tregs in blood, lymph nodes and spleen, but did increase the number of effector Tregs (CD44⁺CD62L^-) in lymph nodes. Importantly, in both rats and mice with DR, SR2211 reduced retinal vascular leakage and VEGF protein levels compared to diabetic controls. In diabetic rats, the mRNA levels of the inflammatory factors, tumour necrosis factor (TNF) and intracellular adhesion molecule (ICAM)-1 in retina were reduced by SR2211.

Conclusions : Conclusion: RORγ inhibition attenuates DR by reducing pro-inflammatory Th17 cells and boosting the functionality of Tregs.

This is a 2021 ARVO Annual Meeting abstract.