Interleukin-35 Suppresses Pyroptosis and Protects Neuronal Death in Retinal Ischemia/Reperfusion Injury

Abstract Background: Retina ischemia-reperfusion (I/R) is a pathological process in many eye disorders. Neuroinflammation and cell pyroptosis have been recognized as important in the pathogenesis of tissue damage in retina I/R. Interleukin (IL)-35 is a novel heterodimeric cytokine that exhibits anti-inflammatory activity in virous autoimmune diseases, but its role in retina I/R and the underlying molecular mechanisms remain unexplored. This study investigated the effect of IL-35 on retina I/R and the inhibition of pyroptosis and neuronal death.Methods: A murine retina I/R model was used to explore the neuroprotective effect of IL-35 recombinant protein in vivo. The primary murine microglial cells of pyroptosis and the retinal ganglion cells (RGCs) of oxygen and glucose deprivation/reoxygenation (OGD/R) models were employed to test the anti-pyroptotic and anti-apoptotic effects of IL-35 in vitro.Result: We found that IL-35 decreases retinal damage, RGC death, and inner plexiform layer (IPL) thinning in mice with retinal I/R injury, with significant attenuation of pyroptosis in the retina. The data also demonstrated the anti-pyroptosis action of IL-35 in primary microglia stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Furthermore, primary RGC apoptosis induced by OGD/R was directly suppressed by IL-35, and the IL-35-mediated neuroprotection was abrogated when miR-21 was blocked.Conclusion: Our findings identify potential underlying mechanisms of RGC apoptosis and suggest a new therapeutic target, IL-35, which exerts a robust neuroprotective effect against retina I/R.