Abstract:

Inflammation is a complex and highly regulated response that occurs early after infection or injury. The inflammatory response in the central nervous system (CNS), known as neuroinflammation, is achieved by activation of resident glia and monocyte-derived cells. Accumulating evidence indicates that this cellular response occurs in the early stages of numerous neurodegenerative diseases, triggering a cascade of events that converge to promote neuronal damage. Indeed, neuroinflammation has been reported in a host of CNS disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, stroke, and glaucoma. Glaucoma is a prevalent neurodegenerative disease and characterized by the progressive degeneration of retinal ganglion cells (RGC) and their axons in the optic nerve resulting in gradual vision loss. High intraocular pressure is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure promotes RGC damage is currently unknown. Current therapies are aimed at lowering intraocular pressure, but many patients continue to experience visual field loss even when pressure lowering treatments are implemented. A better understanding of the mechanisms causing glaucomatous neurodegeneration triggered by ocular hypertension injury is, therefore, essential to develop effective therapies. Accumulating evidence indicates that neuroinflammation plays a key role in RGC damage in glaucoma. A number of studies have confirmed the presence of hallmark features of neuroinflammation in glaucoma animal models and human specimens including glial cell activation, upregulation of proinflammatory cytokines, induction of the complement cascade, and trans-endothelial cell migration of leukocytes. A critical modulator of the neuroinflammatory response in glaucoma is tumor necrosis factor alpha (TNFα). RGCs express the TNFα receptors 1 and 2 (TNFR1/2) and TNFα signaling has been linked to RGC death. For example, exogenous administration of TNFα promotes RGC loss and optic nerve degeneration, and genetic or pharmacological depletion of TNFα or its receptors stimulates RGC survival. High-throughput characterization of the retinal proteome revealed significant upregulation of TNFα signaling in human glaucoma. Notably, TNFα levels are elevated in aqueous humor samples from glaucoma patients and TNFα gene polymorphisms are associated with primary open angle glaucoma. In conclusion, while endogenous TNFα plays critical physiological roles in retinal homeostasis and neurotransmission. These findings suggest that modulation of soluble TNFα signaling might be beneficial to counter the harmful effect of neuroinflammation and synaptic alterations in glaucomatous optic neuropathies.