TNF-α signaling in glaucomatous neurodegeneration

Abstract

Growing evidence supports the role of TNF-α as a mediator of neurodegeneration in glaucoma. Glial production of TNF-α is increased and its death receptor is up-regulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. Opposing these cell-death promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-α as best exemplified by differential responses of RGCs and glia. In addition to the direct neurotoxicity of TNF-α to RGCs and their axons, potential interplay of TNF-α signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to secondary neurodegenerative injury. This review focuses on the present evidence supporting the involvement of TNF-α signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.

How strong is the relationship between glaucoma, the retinal nerve fibre layer, and neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis?

“…These mechanisms include neuroinflammation, 40 high levels of tumour necrosis factor alpha, 41,42 and upregulation of complement component 1q. 43,44 In addition, AB 1-42 and tau protein have been implicated in the pathogenesis of both AD and glaucoma.…”

Assesment of the Retinal Nerve Fiber Layer Thickness with Optical Coherence Tomography in Patients with Psoriasis

“…Glokomun henüz asemptomatik olduğu dönemde bile OKT yöntemi ile saptanan ortalama RSLT kalınlıklarının azalmış olarak bulunması, asemptomatik optik sinir dejenerasyonunun saptanmasında OKT yöntemini değerli kılmaktadır (10 (20). Halbuki psoriasis patogenezinde de önemli yeri olan TNF α'nın deneysel modellerde retina üzerinde nörodejeneratif etki gösterdiği gösterilmiştir (21). Psoriasis hastalarında TNF α'nın nörodejeneratif etkisine karşı NGF ve VEGF gibi sitokinler retina başta olmak üzere nöral dokularda koruyucu etki gösteriyor olabilir.…”

Retinal Ganglion Cell Death

“…Glial production of tumor necrosis factor-α (TNF-α) is increased, and the level of TNF receptor-1 upregulated, in RGCs and their axons in glaucomatous donor eyes [Tezel G, 2008]. The two main subgroups of the TNF receptor superfamily, TNF-R1 and TNF-R2, recognize both the membrane-bound and soluble forms of TNF-α.…”

“…This factor, secreted by stressed glial cells within glaucomatous tissues, can induce RGC death via induction of a receptor-mediated caspase cascade, mitochondrial dysfunction, and/or oxidative damage. In addition to direct neurotoxic effects on RGCs and axons thereof, TNF-α signaling is likelyto contribute to secondary degeneration of primarily uninjured RGCs [Tezel G, 2008]. TNF-α can induce glial NO production thus the extent of excitotoxic injury.…”

“…TNF-α signaling may be associated with axonal dysfunction and Wallerian degeneration. One function of TNF-α during the latter type of degeneration has been suggested to be induction of macrophage recruitment for debris removal [Tezel G, 2008]. TNF-α also activates matrix metalloproteinases, which are involved in tissue remodeling within the glaucomatous optic nerve head.…”