Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-␣ (TNF-␣) may contribute to the disease process, although its role in vivo and its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-␣, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-␣ injections in normal mice mimicked these effects. Conversely, an anti-TNF-␣-neutralizing antibody or deleting the genes encoding TNF-␣ or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-␣ provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-␣ signaling or inflammation, therefore, may be helpful in treating glaucoma.
Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspasedependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders.degenerations | necroptosis P hotoreceptor death and subsequent visual decline occurs when the photoreceptors are separated from the underlying retinal pigment epithelium. Physical separation of photoreceptors is seen in various retinal disorders, including age-related macular degeneration (1), diabetic retinopathy (2), as well as rhegmatogenous (i.e., caused by a break in the retina) retinal detachment (3, 4). Although surgery is carried out to reattach the retina, only two fifths of patients with rhegmatogenous retinal detachment involving the macula, a region essential for central vision, recover 20/40 or better vision because of photoreceptor death (4, 5). Thus, identification of the mechanisms that underlie photoreceptor death is critical to developing new treatment strategies for these diseases.Apoptosis and necrosis are two major cell death modalities (6). Apoptosis is a highly regulated process involving the caspase family of cysteine proteases. In contrast, necrosis has been considered a passive, unregulated form of cell death; however, recent evidence indicates that some necrosis can be induced by regulated signal transduction pathways such as those mediated by receptor interacting protein (RIP) kinases, especially in conditions in which caspases are inhibited or cannot be activated efficiently (7,8). Stimulation of the Fas and TNFR family of death domain receptors is known to mediate apoptosis in most cell types through the activation of the extrinsic caspase pathway. In addition, in certain cells deficient for caspase-8 or treated with the pan-caspa...
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