Dysfunctional Nurr1 promotes high glucose-induced Müller cell activation by up-regulating the NF-κB/NLRP3 inflammasome axis.

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.