TNF-alpha signaling in glaucomatous neurodegeneration

Abstract

Growing evidence supports the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of neurodegeneration in glaucoma. Glial production of TNF-alpha is increased, and its death receptor is upregulated 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. In addition to direct neurotoxicity, potential interplay of TNF-alpha signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to spreading neuronal damage by secondary degeneration. 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-alpha as best exemplified by differential responses of RGCs and glia. This review focuses on the present evidence supporting the involvement of TNF-alpha signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.

Figure 1

Binding of TNF-α to TNF-R1, a death receptor, can induce RGC death through receptor-mediated caspase activation, and caspase-dependent and -independent components of the mitochondrial cell death pathway, which includes increased generation of ROS leading to oxidative damage. In addition, ceramide generation and silencing of survival signals have been associated with TNF-α-mediated cell death. Opposing these cell-death promoting signals, binding of TNF-R1 can also trigger the activation of survival signals, which include the activation of a transcription factor, NF-KB, whose target genes include inhibitor-of-apoptosis proteins. Another intrinsic protection mechanism activated after TNF receptor binding involves heat shock proteins. A critical balance between a variety of intracellular signaling pathways determines whether a RGC will die or survive the exposure to TNF-α (TNF-α, tumor necrosis factor-alpha; TNF-R1, TNF death receptor; aif, apoptosis inducing factor; c, cytochrome c; ROS, reactive oxygen species; NF-KB, nuclear factor-kappaB; IKB, NF-KB inhibiting protein).

Figure 2

Glial production of TNF-α is increased in the glaucomatous retina and optic nerve head. In addition to direct neurotoxicity to RGCs and their axons, potential interplay of TNF-α signaling with the other cellular events associated with glaucomatous neurodegeneration likely contributes to secondary degeneration of primarily uninjured RGCs. Glaucomatous tissue stress and activation of the immune-regulatory function of glial cells may also facilitate the initiation of an immune response. TNF-α is one of the most abundant cytokines produced by reactive T cells and appears to play a major role in T cell-mediated neurotoxicity.