Role of Interleukin-21 in retinal ischemia-reperfusion injury: Unveiling the impact on retinal ganglion cell apoptosis

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. 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. 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. 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.