Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). During DR, high glucose levels induce Müller cell gliosis, and the dysfunction of Müller cells further promotes the pathogenesis of DR. Transcription factor nuclear receptor subfamily 4 group A member 2 (Nurr1) inhibits the inflammatory response by suppressing nuclear factor-kappa B (NF-κB) and downregulating the downstream NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome. This study aimed to investigate whether Nurr1 dysfunction in Müller cells promoted the NF-κB/NLRP3 inflammasome axis during DR. In vitro, Nurr1 expression and nuclear translocation decreased in Müller cells exposed to high glucose levels; therefore, p65 was activated, and the downstream NLRP3 inflammasome was up-regulated via the interaction of p65 with its promoter. These phenomena promoted Müller cell activation and proliferation. Moreover, in vivo, gavage of the Nurr1 agonist C-DIM12 reduced retinal ganglion cell (RGC) loss in a mouse model of streptozotocin (STZ)-induced diabetes. Together, these results showed that Nurr1 played important anti-inflammatory and neuroprotective roles in Müller cells during DR, suggesting that Nurr1 may be a potential molecular target for the treatment of DR.

中文翻译：

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功能失调的 Nurr1 通过上调 NF-κB/NLRP3 炎性体轴促进高糖诱导的 Müller 细胞活化

糖尿病视网膜病变 (DR) 是糖尿病 (DM) 最常见的微血管并发症。DR 期间，高糖水平诱导 Müller 细胞胶质增生，Müller 细胞功能障碍进一步促进 DR 的发病。转录因子核受体亚家族 4 组 A 成员 2 (Nurr1) 通过抑制核因子-κB (NF-κB) 和下调下游 NACHT、LRR 和 PYD 结构域蛋白 3 (NLRP3) 炎症小体来抑制炎症反应。本研究旨在调查 Müller 细胞中的 Nurr1 功能障碍是否在 DR 期间促进了 NF-κB/NLRP3 炎性体轴。在体外，暴露于高葡萄糖水平的 Müller 细胞中 Nurr1 表达和核易位降低；因此，p65 被激活，下游 NLRP3 炎症小体通过 p65 与其启动子的相互作用上调。这些现象促进了穆勒细胞的活化和增殖。此外，在体内，在链脲佐菌素 (STZ) 诱导的糖尿病小鼠模型中，灌胃 Nurr1 激动剂 C-DIM12 减少了视网膜神经节细胞 (RGC) 的丢失。总之，这些结果表明 Nurr1 在 DR 期间在 Müller 细胞中发挥重要的抗炎和神经保护作用，表明 Nurr1 可能是治疗 DR 的潜在分子靶点。