Glial Cells in Glaucoma: Friends, Foes, and Potential Therapeutic Targets

García‐Bermúdez, Mariana Yolotzin; Freude, Kristine; Mouhammad, Zaynab Ahmad; Wijngaarden, Peter van; Martin, K.; Kolko, Miriam

doi:10.3389/fneur.2021.624983

Cited by 60 publications

(45 citation statements)

References 223 publications

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Section: Glaucomamentioning

confidence: 99%

“…Glaucoma is one of the main causes of blindness worldwide, which is estimated to affect more than 120 million people by 2040 [114]. It is characterised by the gradual loss of RGCs and, like AD and PD, significant neurodegeneration would have already occurred before clinical symptoms start to emerge [114]. Numerous methods for detecting the activity of glaucoma have been developed, including elevated intraocular pressure and an increased numbers of dying retinal cells, which is measured by detecting apoptosing retinal cells (DARC) [115,116].…”

Section: Glaucomamentioning

confidence: 99%

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Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

Choi¹,

Guo²,

Cordeiro

2021

Cells

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Microglia are the resident immune cells of the central nervous system (CNS), including the retina. Similar to brain microglia, retinal microglia are responsible for retinal surveillance, rapidly responding to changes in the environment by altering morphotype and function. Microglia become activated in inflammatory responses in neurodegenerative diseases, including multiple sclerosis (MS). When activated by stress stimuli, retinal microglia change their morphology and activity, with either beneficial or harmful consequences. In this review, we describe characteristics of CNS microglia, including those in the retina, with a focus on their morphology, activation states and function in health, ageing, MS and other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, glaucoma and retinitis pigmentosa, to highlight their activity in disease. We also discuss contradictory findings in the literature and the potential ways of reducing inconsistencies in future by using standardised methodology, e.g., automated algorithms, to enable a more comprehensive understanding of this exciting area of research.

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Section: Glaucomamentioning

confidence: 99%

Section: Glaucomamentioning

confidence: 99%

Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

Choi¹,

Guo²,

Cordeiro

2021

Cells

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“…Astrocytes, microglia, and Müller cells are the three major types of retinal glial cells, with the contribution by astrocytes and microglia particularly relevant to inflammation found with glaucoma ( Wei et al, 2019 ; García-Bermúdez et al, 2021 ). Microglia are innate immune cells residing throughout the retina, ON, and brain.…”

Section: Glia Contribute To Inflammatory Responses In Glaucomamentioning

confidence: 99%

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

2021

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Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1β and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1β release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer’s and Parkinson’s disease.

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“…Müller glial cells (MGCs), which together with astrocytes form a part of retinal macroglia, play an important role in maintaining retinal homeostasis by supervising the ionic exchange and the response to neurotrophic molecules [ 143 , 144 ]. Moreover, MGCs exert a real neuroprotective effect by releasing NTs and carrying out antioxidant functions, as well as regulating neuronal signaling by recycling neurotransmitters [ 145 ].…”

Section: Neuroprotectionmentioning

confidence: 99%

Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention

Vernazza

Oddone

Tirendi

et al. 2021

IJMS

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Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.

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Glial Cells in Glaucoma: Friends, Foes, and Potential Therapeutic Targets

Cited by 60 publications

References 223 publications

Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

Risk Factors for Retinal Ganglion Cell Distress in Glaucoma and Neuroprotective Potential Intervention

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