Review articleGlaucoma and neuroinflammation: An overview
Introduction
Glaucoma, the second leading cause of blindness worldwide,87 is characterized by progressive optic nerve head (ONH) damage and visual field impairment.55 Degeneration of retinal ganglion cells (RGCs), loss of their axons, and damage and remodeling of the lamina cribrosa are the main events of glaucoma pathogenesis.51
A number of converging molecular pathways are involved in RGC death, potentially triggered and exacerbated by risk factors such as elevated intraocular pressure (IOP),48,62,130 age,99,100 ocular biomechanics131 and low ocular perfusion pressure.149 Among these, elevated IOP is the only evidence-based modifiable factor clearly associated with glaucoma. Nevertheless, elevated IOP may also be present in healthy individuals,56 whereas glaucoma characterized by IOP within normal range (normal-tension glaucoma) is a well-known entity.
Apoptosis is the primary mechanism of RGC death in glaucoma, although little is known about the signals triggering and sustaining this process.150 Apoptosis may be initiated by signaling pathways in the RGC soma and axon and/or in the extracellular environment. Recently, growing evidence accumulated on the importance of macro- and microglia in the process of both apoptosis activation and continuation.203 Increased IOP may have a neuroinflammation-promoting effect on glial environment, with individual susceptibility possibly determined by genetic and/or epigenetic factors.151,222 Reorganization of the glia induced by differential gene expression could function as a first attempt to isolate and resolve the neural stress;202 however, chronically activated glia may lose their supportive role, making RGCs and their axons more vulnerable to damage128 and consequently more prone to apoptosis.
We review recent evidence on neuroinflammation as it relates to glaucoma by highlighting the link between neuroinflammation and RGC death, both in early and more advanced stages of the disease.
Section snippets
The effects of IOP on the retina and retinal ganglion cells
Glaucoma has been associated with retinal vascular dysregulation,50,57 and previous studies using optical coherence tomography angiography (OCT-A) have shown a reduction of retinal vessel density in the eyes of glaucomatous patients,217 although robust longitudinal studies are needed to clarify whether the ONH blood flow changes precede or follow the nerve structural damages.235 The effect of IOP on the retina vascular regulation is still debated.217,229 It was demonstrated that an acute
Conclusions
The exact mechanism leading to RGC death in glaucoma is still to be clarified.92 Recently, evidence has accumulated that neuroinflammation may play an important role in the disease initial stages, as well in its progression. Activated neuroinflammatory pathways may be initially directed to restore the homeostasis between RGCs and the extracellular environment, with protective effects; however, chronic inflammation, with over-production of chemokines, cytokines, and activation of innate
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luciano Quaranta: Fee/Honoraria from Allergan, Bausch&Lomb, Novartis, Thea, Santen, Visufarma; Consultancy for Fidia-Sooft, Visufarma; Travel/Research grant from Allergan, Bausch&Lomb, Omikron, Novartis, Santen, SIFI. Carlo Bruttini: None; Eleonora Micheletti: None; Anastasios G.P. Konstas: Research funding from Allergan, Bayer, Omni Vision, Pharmaten and
Acknowledgments
The contribution of IRCCS Fondazione Bietti was supported by the Italian Ministry of Health and by Fondazione Roma.
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