Elsevier

Survey of Ophthalmology

Volume 66, Issue 5, September–October 2021, Pages 693-713
Survey of Ophthalmology

Review article
Glaucoma and neuroinflammation: An overview

https://doi.org/10.1016/j.survophthal.2021.02.003Get rights and content

Abstract

Glaucoma is an optic neuropathy characterized by well-defined optic disc morphological changes (i.e., cup enlargement, neuroretinal border thinning, and notching, papillary vessel modifications) consequent to retinal ganglion cell loss, axonal degeneration, and lamina cribrosa remodeling. These modifications tend to be progressive and are the main cause of functional damage in glaucoma. Despite the latest findings about the pathophysiology of the disease, the exact trigger mechanisms and the mechanism of degeneration of retinal ganglion cells and their axons have not been completely elucidated. Neuroinflammation may play a role in both the development and the progression of the disease as a result of its effects on retinal environment and retinal ganglion cells. We summarize the latest findings about neuroinflammation in glaucoma and examine the connection between risk factors, neuroinflammation, and retinal ganglion cell degeneration.

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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