靶向RORγ促进调节性T细胞和改善小鼠糖尿病视网膜病变。

IF 3.6 2区 医学 Q1 PATHOLOGY
Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L Wilkinson-Berka
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引用次数: 0

摘要

糖尿病视网膜病变是导致失明的主要原因之一,其特征是视网膜脉管系统受损,其中T细胞介导的炎症越来越被认为是一个重要的因素。视黄酸受体相关孤儿受体γ (RORγ)在调节表达转录因子Foxp3的抗炎调节性T细胞(Tregs)和促炎Th17细胞之间的平衡中起关键作用。我们假设SR2211抑制RORγ,同时靶向RORγ及其亚型RORγ γt,可以增加Tregs并减少Th17细胞,从而减少链佐菌素诱导的糖尿病视网膜病变模型中的炎症和血管病变。将表达Foxp3为红色荧光蛋白的小鼠用SR2211治疗糖尿病26周,并与糖尿病小鼠和非糖尿病对照组小鼠进行比较。在糖尿病小鼠的血液和淋巴组织中,用SR2211治疗可以恢复treg的数量,并将Th17细胞降低到糖尿病小鼠+对照体的水平。在糖尿病小鼠的视网膜中,与糖尿病小鼠+对照体相比,SR2211处理增加了Tregs,降低了小胶质细胞的活化,降低了促炎因子(包括白细胞介素- 17a、白细胞介素-6和肿瘤坏死因子)的表达,降低了血管渗漏、血管内皮生长因子和脱细胞毛细血管的表达。这些发现表明,RORγ/RORγ γt抑制能够调节特异性t细胞反应,抑制小胶质细胞激活,从而减少糖尿病视网膜病变的炎症和血管损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting RORγ to boost regulatory T cells and ameliorate diabetic retinopathy in mice.

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.

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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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