Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China.
Shanghai Jiaotong University School of Medicine, Shanghai, China.
FASEB J. 2021 Apr;35(4):e21184. doi: 10.1096/fj.202000645RR.
Amyloid β (Aβ) is a crucial component of drusen, the hallmark of the early stage of age-related macular degeneration (AMD), and can cause retinal pigment epithelium (RPE) cell damage through activation of the inflammatory response. MicroRNAs play a critical role in inflammation. However, the mechanism underlying the effect of microRNAs on the NLRP3 inflammasome induced by Aβ remains poorly understood. In the present study, we demonstrated that Aβ -mediated RPE damage by inducing a decrease in endogenous miR-191-5p expression. This led to the upregulation of its target gene, C/EBPβ. C/EBPβ acts as a transcription factor for NLRP3, promotes its transcription, and upregulates the downstream inflammatory factors Caspase-1 and IL-1β. Correspondingly, overexpression of miR-191-5p alleviated RPE cell injury by suppressing inflammation. The present study elucidates a novel transcriptional regulatory mechanism of the NLRP3 inflammasome. Our findings suggest an anti-inflammatory effect of miR-191-5p in Aβ -induced RPE impairment, shedding light on novel preventive or therapeutic approaches for AMD-associated RPE impairment.
淀粉样蛋白 β（Aβ）是 年龄相关性黄斑变性（AMD）早期阶段的特征性 drusen 的关键成分，可通过炎症反应的激活引起视网膜色素上皮（RPE）细胞损伤。微小 RNA（miRNA）在炎症中发挥着关键作用。然而，miRNA 对 Aβ 诱导的 NLRP3 炎性小体的影响机制仍知之甚少。本研究表明，Aβ 通过诱导内源性 miR-191-5p 表达降低介导 RPE 损伤。这导致其靶基因 C/EBPβ 的上调。C/EBPβ 作为 NLRP3 的转录因子，促进其转录，并上调下游炎症因子 Caspase-1 和 IL-1β。相应地，miR-191-5p 的过表达通过抑制炎症减轻 RPE 细胞损伤。本研究阐明了 NLRP3 炎性小体的一种新的转录调控机制。我们的研究结果表明 miR-191-5p 在 Aβ 诱导的 RPE 损伤中具有抗炎作用，为 AMD 相关 RPE 损伤的新型预防或治疗方法提供了新的思路。
