背景:视网膜缺血再灌注(I/R)是眼部疾病的重要原因,引发一系列病理过程。神经炎症和视网膜神经节细胞(RGC)凋亡之间的相互作用是视网膜I/R诱导的组织损伤的一个很好的探索方面。在这个错综复杂的景观中,炎性细胞因子白细胞介素-21(IL21)作为神经炎症的有效介质出现,对神经元完整性具有已知的有害影响。然而,其在视网膜I/R背景下对RGC凋亡的具体影响仍有待发现。本研究旨在揭示IL21siRNA对RGC的潜在抗凋亡作用。发光对视网膜I/R的神经保护作用
方法:Sprague-Dawley(SD)大鼠接受控制性的眼内压(IOP)升高至110mmHg60分钟,以模拟视网膜I/R条件。探讨IL21对RGC细胞凋亡的影响及其分子机制,一系列全面的技术,如免疫组织化学,免疫荧光,TUNEL,苏木精-伊红(H&E),免疫印迹,并进行qRT-PCR。
结果:视网膜I/R损伤的景观显示IL21的表达增加,在72h达到峰值。IL21在视网膜I/R环境内显着诱导RGC凋亡。IL21siRNA的引入显示了有希望的结果,表现为神经功能缺损的改善,RGC损失的减少,和72小时再灌注时视网膜内层的厚度增加。此外,IL21siRNA证明了其通过JAK/STAT信号通路阻止与细胞凋亡相关的蛋白质释放的能力。在体外环境中,IL21siRNA通过调节JAK/STAT信号通路抑制与凋亡相关的蛋白质的产生,从而有效地减少R28细胞凋亡。
结论:这项研究为IL21在视网膜I/R中的致病作用提供了证据。该发现强调了IL21siRNA作为缺血性视网膜损伤的有希望的治疗靶标。其功效在于其通过抑制JAK/STAT信号通路减轻RGC凋亡的能力。这些发现不仅增强了我们对视网膜I/R病理学的理解,而且还表明IL21siRNA在缺血性视网膜损伤的靶向治疗的开发中作为潜在的转化因子。
BACKGROUND: Retinal ischemia-reperfusion (I/R) serves as a significant contributor to ocular diseases, triggering a cascade of pathological processes. The interplay between neuroinflammation and the apoptosis of retinal ganglion cell (
RGC) is a well-explored aspect of retinal I/R-induced tissue damage. Within this intricate landscape, the inflammatory cytokine Interleukin-21 (IL21) emerges as a potent mediator of neuroinflammation with known detrimental effects on neuronal integrity. However, its specific impact on
RGC apoptosis in the context of retinal I/R has remains to be uncovered. This study aims to unravel the potential anti-apoptotic effects of IL21 siRNA on
RGC, shedding light on the neuroprotection of retinal I/R.
METHODS: Sprague-Dawley (SD) rats underwent a controlled elevation of intraocular pressure (IOP) to 110 mmHg for 60 min to simulate retinal I/R conditions. To explore the influence of IL21 on RGC apoptosis and its underlying molecular mechanisms, a comprehensive array of techniques such immunohistochemistry, immunofluorescence, TUNEL, Hematoxylin-eosin (H&E), immunoblotting, and qRT-PCR were carried out.
RESULTS: The landscape of retinal I/R injury revealed an increase in the expression of IL21, reaching its peak at 72 h. Notably, IL21 markedly induced
RGC apoptosis within the retinal I/R milieu. The introduction of IL21 siRNA showed promising outcomes, manifesting as an amelioration of neurological function deficits, a reduction in
RGC loss, and an increase in the thickness of the inner retinal layer at the 72-hour reperfusion. Additionally, IL21 siRNA demonstrated its ability to hinder the release of proteins associated with apoptosis via the JAK/STAT signaling pathway. In the in vitro setting, IL21 siRNA efficiently reduced R28 cell apoptosis by suppressing the production of proteins associated with apoptosis by regulating the JAK/STAT signaling pathway.
CONCLUSIONS: This study provides evidence for the pathogenic role of IL21 in retinal I/R. The findings underscore IL21 siRNA as a promising therapeutic target for ischemic retinal injury. Its efficacy lies in its ability to mitigate RGC apoptosis by suppressing the JAK/STAT signaling pathway. These findings not only enhance our comprehension of retinal I/R pathology but also suggests IL21 siRNA as a potential transformative factor in the development of targeted therapies for ischemic retinal injuries.