Multiple types of programmed necrosis such as necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos contribute simultaneously to retinal damage after ischemia–reperfusion

Abstract

Ischemia–reperfusion (IR) injury is implicated in a large array of pathological conditions in the retina. Increasing experimental evidence suggests that programmed necrosis makes a significant contribution to inflammation and retinal damage triggered by IR. Since there are many types of programmed necrosis, it is important to identify those involved in retinal IR to determine the correct treatment. To this end, we used a mouse model of retinal IR and a variety of approaches including RNA-seq data analysis. Our RNA-seq data revealed the rapid development of ischemic pathology in the retina during the first 24 h after reperfusion. We found that at least four types of programmed necrosis including necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos are simultaneously involved in retinal IR. Our data suggest that the high activity of the TNF pathway at the early stage of retinal IR leads to early activation of necroptosis while significant activity of other types of programmed necrosis appears later. Our results indicate that TNF, glutamate, and ferrous iron generated by Steap3 may be key players concurrently triggering at least necroptosis, oxytosis/ferroptosis, and parthanatos in ischemic retinal ganglion cells (RGCs). Thus, multiple signaling cascades involved in programmed necrosis should be synchronously targeted for therapeutic purposes to treat retinal IR.

Various forms of programmed cell death, including apoptosis and regulated necrosis, are concurrently activated in retinal ganglion cells after ischemia and reperfusion

“…4). Previously published studies support this observation (Dvoriantchikova et al, 2022;Qin et al, 2022;Yao et al, 2022). While individually ROS and ferrous iron (Fe2+) do not pose a threat to the cell, their simultaneous presence in the cell are a "thermonuclear mix" that starts an uncontrolled production of ROS in the ferrous iron (Fe2+)-controlled Fenton/Haber-Weiss reaction (Koppenol, 2001;Liochev and Fridovich, 2002) ).…”

“…In this regard, a recent study by Qin et al is so important, indicating that several forms of cell death -apoptosis, necroptosis, and oxytosis/ferroptosis -are activated simultaneously in ischemic RGCs; concurrent inhibition of these forms of cell death led to a signi cant survival of ischemic RGCs compared to when each form of cell death was inhibited separately (Qin et al, 2022). Our recent study indicates that many forms of regulated necrosis, including necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos, are concurrently triggered in the retina after IR (Dvoriantchikova et al, 2022). The disadvantage of this study was that it was carried out on the entire retina and thus it was di cult to unequivocally state that all these regulated necrosis pathways are simultaneously activated in only RGCs and not in other retinal cell types.…”

“…5B). The role of TNFR1 (Tnfrsf1a) in RGC death after retinal IR has already been shown (Fontaine et al, 2002;Dvoriantchikova et al, 2022). However, the role of other death receptors in RGC death after retinal IR has not yet been understood.…”

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia–Reperfusion in the Eyes of Sprague Dawley Rats

“…A similar protective effect is a hallmark of other anti-ischemic agents as well [ 31 , 32 , 49 ]. It is well documented that a common consequence of ischemia–reperfusion injury is edema [ 46 , 50 ], and then necro-apopto-autophagy, i.e., initiation of different cell-death mechanisms, resulting in thinning of retinal layers [ 47 , 51 , 52 ]. Edema, however, may be transient, which implies a reversible injury as well [ 46 , 53 ].…”

The scheme, and regulative mechanism of pyroptosis, ferroptosis, and necroptosis in radiation injury

“…While apoptosis has traditionally been regarded as the primary mechanism of cell death, the recognition of alternative forms, such as programmed necrosis, has challenged this conventional perspective 35 , 36 . Pyroptosis 37 , 38 , ferroptosis 39 , 40 , and necroptosis 41 , 42 , which have gained significant attention in recent years, fall under the category of programmed cell necrosis.…”