Various Forms of Programmed Cell Death Are Concurrently Activated in the Population of Retinal Ganglion Cells after Ischemia and Reperfusion

Abstract

Retinal ischemia–reperfusion (IR)—which ultimately results in retinal ganglion cell (RGC) death—is a common cause of visual impairment and blindness worldwide. IR results in various types of programmed cell death (PCD), which are of particular importance since they can be prevented by inhibiting the activity of their corresponding signaling cascades. To study the PCD pathways in ischemic RGCs, we used a mouse model of retinal IR and a variety of approaches including RNA-seq analysis, knockout animals, and animals treated with an iron chelator. In our RNA-seq analysis, we utilized RGCs isolated from retinas 24 h after IR. In ischemic RGCs, we found increased expression of many genes that regulate apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos. Our data indicate that genetic ablation of death receptors protects RGCs from IR. We showed that the signaling cascades regulating ferrous iron (Fe2+) metabolism undergo significant changes in ischemic RGCs, leading to retinal damage after IR. This data suggests that the activation of death receptors and increased Fe2+ production in ischemic RGCs promote the simultaneous activation of apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos pathways. Thus, a therapy is needed that concurrently regulates the activity of the multiple PCD pathways to reduce RGC death after IR.

Molecular mechanisms of NMDA excitotoxicity in the retina

“…Meanwhile, inactivation of this cascade leads to significant RGC survival in NMDA treated retinas. Our data and the results of other investigators indicate that there is significant RGC death in the presence of the Tnf cytokine in vivo and in vitro 8 , 22 – 24 , 31 , 36 – 39 . It has also been shown that inhibition of this cytokine leads to significant RGC survival after NMDA treatment 8 .…”

“…To evaluate the significance of these data, we used the oral iron chelator deferiprone (DFP). It has previously been shown that DFP significantly reduces the level of labile iron in the retina, protecting it from many pathologies 26 – 31 . We expected that lowering labile iron would lead to reduced NMDA excitotoxicity.…”

Modeling of Retina and Optic Nerve Ischemia–Reperfusion Injury through Hypoxia–Reoxygenation in Human Induced Pluripotent Stem Cell-Derived Retinal Ganglion Cells

“…Ischemia-induced RGC degeneration involves multiple complex cell death pathways [7]. It has been reported that proteins involved in necroptosis (Ripk1 and Ripk3) are present in the retina and that the suppression of these proteins prevents necrosis caused by ischemia-reperfusion and increases RGC survival [8].…”