FXR suppress Müller cell activation by regulating cGAS/STING pathway in diabetic retinopathy.

Abstract

Diabetic retinopathy (DR) is widely acknowledged as an ocular complication of diabetes mellitus involving retinal inflammation and secondary neuro/microvascular degeneration. Müller glial cells play a crucial role in regulating retinal homeostasis and neuroinflammation within the retina. Farnesoid X nuclear receptor (FXR) has emerged as a potential regulator of metabolic homeostasis and inflammatory responses as a bile acid nuclear receptor. However, its precise role in DR remains unclear. In order to investigate the effect of FXR on DR, we employed Sprague-Dawley rats treated with streptozotocin (STZ) and human Müller glial cells treated with advanced glycation end products (AGEs) or high glucose with palmitate (HG + PA). Our investigations revealed downregulation of FXR in DR. Furthermore, we demonstrated that activating FXR could mitigate the progression of DR, with its protective effects linked to the inhibition of inflammatory responses within Müller cells. Mechanistically, FXR could ameliorate mitochondrial dysfunction and suppress the opening of the mitochondrial permeability transition pore. This action blocked the release of mitochondrial DNA (mtDNA) from the mitochondria into the cytoplasm, thereby inhibiting the abnormal activation of the cGAS/STING pathway in DR. Further studies revealed that FXR upregulates mitochondrial transcription factor A (TFAM) by modulating ATF4/NRF1, ultimately enhancing mitochondrial function. Knockdown of FXR reversed the above effects. Additionally, FXR activation effectively rescued mitochondrial dysfunction, as evidenced by Tunicamycin (TUN)-mediated assays, further validating our findings. In summary, our findings suggest that targeting FXR may offer promising strategies for future therapeutic interventions in the treatment of DR.