Progress in Retinal and Eye Research

Progress in Retinal and Eye Research 83 (2021) 100916
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Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/preteyeres
Inflammation in Glaucoma: From the back to the front of the eye,

and beyond
Christophe Baudouin a, b, c, *, 1, Miriam Kolko d, e, 1, Stéphane Melik-Parsadaniantz b, 1,
Elisabeth M. Messmer f, 1
a
Quinze-Vingts National Ophthalmology Hospital, INSERM-DGOS CIC 1423, IHU Foresight, Paris, France
b
Sorbonne Université, INSERM, CNRS, Institut de La Vision, Paris, France
c
Department of Ophthalmology, Ambroise Paré Hospital, APHP, Université de Versailles Saint-Quentin en Yvelines, Boulogne-Billancourt, France
d
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
e
Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet-Glostrup, Glostrup, Denmark
f
Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
A R T I C L E I N F O A B S T R A C T
Keywords: The pathophysiology of glaucoma is complex, multifactorial and not completely understood. Elevated intraocular
Benzalkonium chloride pressure (IOP) and/or impaired retinal blood flow may cause initial optic nerve damage. In addition, age-related
Inflammation oxidative stress in the retina concurrently with chronic mechanical and vascular stress is crucial for the initiation
IOP-Lowering drugs
of retinal neurodegeneration. Oxidative stress is closely related to cell senescence, mitochondrial dysfunction,
Neuroinflammation
Ocular surface
excitotoxicity, and neuroinflammation, which are involved in glaucoma progression. Accumulating evidence
Optic-nerve head degeneration from animal glaucoma models and from human ocular samples suggests a dysfunction of the para-inflammation
Oxidative stress in the retinal ganglion cell layer and the optic nerve head. Moreover, quite similar mechanisms in the anterior
Para-inflammation chamber could explain the trabecular meshwork dysfunction and the elevated IOP in primary open-angle
Preservatives glaucoma. On the other hand, ocular surface disease due to topical interventions is the most prominent and
Primary open-angle glaucoma visible consequence of inflammation in glaucoma, with a negative impact on filtering surgery failure, topical
Trabecular meshwork treatment efficacy, and possibly on inflammation in the anterior segment. Consequently, glaucoma appears as an
Treatment
outstanding eye disease where inflammatory changes may be present to various extents and consequences along
the eye structure, from the ocular surface to the posterior segment, and the visual pathway. Here we reviewed the
inflammatory processes in all ocular structures in glaucoma from the back to the front of the eye and beyond. Our
approach was to explain how para-inflammation is necessary to maintain homoeostasis, and to describe
abnormal inflammatory findings observed in glaucomatous patients or in animal glaucoma models, supporting
the hypothesis of a dysregulation of the inflammatory balance toward a pro-inflammatory phenotype. Possible
anti-inflammatory therapeutic approaches in glaucoma are also discussed.
1. Introduction and cupping of the optic disc (Weinreb et al., 2014). Glaucoma repre
sents a group of heterogeneous diseases with varying clinical features
Glaucoma is a multifactorial progressive neurodegenerative disease including risk factors and interrelated mechanisms. Age, increased
that constitutes the most frequent cause of irreversible blindness. It was intraocular pressure (IOP), and a genetic background are the leading risk
recently estimated that the number of people with glaucoma worldwide factors for glaucoma (Weinreb et al., 2014). Primary open-angle glau
will increase from 76.5 million in 2020 to 111.8 million by 2040, mainly coma (POAG) is the most prevalent form in Western countries. However,
due to the aging population (Tham et al., 2014; Kolko et al., 2015a; 30–40% of Caucasian patients with POAG, and an even greater pro
Harasymowycz et al., 2016). Glaucoma is characterised by the loss of portion of the Asian population present with normal tension glaucoma
retinal ganglion cells (RGCs), thinning of the retinal nerve fibre layer, (NTG), typically IOP < 21 mmHg (Esporcatte and Tavares, 2016). Thus,
* Corresponding author. Quinze-Vingts National Ophthalmology Hospital, 28 rue de, Charenton, F-75012, Paris, France.
E-mail address: cbaudouin@15-20.fr (C. Baudouin).
1
Percentage of work contributed by each author in the production of the manuscript is as follows: Christophe Baudouin: 40%, Miriam Kolko: 20%, Stéphane Melik-
Parsadaniantz: 20%, Elisabeth M. Messmer: 20%.
https://doi.org/10.1016/j.preteyeres.2020.100916
Received 7 June 2020; Received in revised form 9 October 2020; Accepted 13 October 2020
Available online 17 October 2020
1350-9462/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
C. Baudouin et al. Progress in Retinal and Eye Research 83 (2021) 100916
the etiology of POAG is generally described as mechanical and/or Therefore, a comprehensive understanding of ocular inflammatory
vascular. The mechanical process involves compression of the axons due mechanisms involved in POAG is necessary before considering potential
to elevated IOP, while the vascular process includes events in which anti-inflammatory therapeutic targets (Benhar et al., 2012). Based on
blood flow and ocular perfusion pressure are reduced to the posterior the scientific literature and our own research in this field, we wanted to
pole leading to damage (Flammer et al., 2002; Mozaffarieh et al., 2008; review the current understanding of inflammatory processes which may
Yanagi et al., 2011; Grzybowski et al., 2020). Vascular or perfusion be involved in POAG from the back to the front of the eye and beyond.
abnormalities in NTG include the increased frequency of migraine
headaches, Raynaud’s phenomenon and sleep apnoea (Shields, 2008). In 2. Inflammation in retinal and optic nerve head degeneration
high IOP glaucoma, it is clear that both the anterior and posterior seg
ments are affected, as extensive damage is detectable in the trabecular The glaucomatous degenerative disease is characterised by a pro
meshwork (TM) and along the inner retina-central visual pathway gressive loss of RGCs, thinning of the retinal nerve fibre layer, and
(Saccà et al., 2016). cupping of the ONH (Jonas et al., 2017). Various stimuli including
Pathogenic mechanisms of the neurodegenerative process induced chronic mechanical stress induced by elevated IOP, hypoxia/ischemia,
by the mechanical and vascular stress involve ischemia/hypoxia (Harris and oxidative stress, coupled with deprivation of neurotrophic factors
et al., 2005), mitochondrial dysfunction, chronic oxidative stress may cause RGC dysfunction and death, especially in aging retina (Vohra
(Chrysostomou et al., 2013; Osborne et al., 2017), excitotoxicity (Leb et al., 2013). It has been suggested that increasing stress over a pro
run-Julien et al., 2009), metabolic stress (Vohra et al., 2019), decreased longed and cumulative period may lead to a failure in the regulation of
levels of nicotinamide (Kouassi Nzoughet et al., 2019; Williams et al., the local protective immune response mediated by glial cells and the
2017a), neurotrophin deprivation (Pease et al., 2000), and neuro complement system, leading to a neuroinflammatory degenerative
inflammation (Russo et al., 2016; Williams et al., 2017b; Jiang et al., process, contributing to disease progression (Tezel, 2011). There is also
2020). Oxidative stress, mitochondrial dysfunction, and cell senescence growing evidence that a loss of immune surveillance and neuro
are increased in the aging retina (Pinazo-Durán et al., 2014; Zhang et al., protection by resident glial cells in the RGC layer and/or the retinal
2015; Sreekumar et al., 2020; Eells, 2019) and are considered among the inner plexiform layer leads to neurodegeneration (Wang et al., 2016).
main glaucoma risk factors. In the aging retina, oxidative stress and lipid
peroxidation are considered the main causes of tissue stress leading to 2.1. Immune surveillance in retinal tissues
the activation of a local para-inflammation of various magnitudes (Xu
et al., 2009). As an immune privilege tissue, the defence system in the retina
Para-inflammation is defined as a tissue adaptive response to noxious consists of retinal immune cells (including microglia, astrocytes and
stress or malfunction, and has characteristics that are considered as in Müller cells) and the complement system (Jiang et al., 2020). Under
termediate between normal/basal and inflammatorye states (Xu et al., normal aging conditions, retinal innate immune cells and the comple
2009). A physiological level of para-inflammation is necessary to ment system undergo a low-grade activation. Para-inflammation is
maintain tissue homeostasis and to restore its functionality, but when induced to rapidly eliminate damaged cells, cell debris and other
tissue is exposed to stress and/or malfunction for a prolonged period, products of the oxidative stress. This is performed through recognition
inflammation may play a deleterious role and be implicated in both and internalisation via scavenger or toll-like receptors (TLRs) expressed
initiation and progression of disease (Medzhitov, 2008). One concept is on glial cells, followed by glial cells activation and the release of com
the dysregulation of para-inflammation, in the retina and other struc plement factors, cytokines/chemokines and apoptotic factors to restore
tures of the eye, in response to stress stimuli especially chronic oxidative the retinal tissue homeostasis (Xu et al., 2009; Xu and Chen, 2016).
stress. Para-inflammation is an important protective homeostatic Sustained oxidative insults for decades is believed to induce a higher
mechanism in the RGC layer and optic nerve head (ONH) which is degree of chronic para-inflammation (Xu et al., 2009; Chen et al., 2019).
dysregulated in glaucoma. Excessive uncontrolled para-inflammation In disease state such as in glaucoma, the para-inflammation response is
may produce inflammatory responses with a marked release of cytoki dysregulated and develops into detrimental inflammation.
nes/chemokines causing irreparable damage to the neuroretina (Chen
et al., 2010). Similar para-inflammatory mechanisms exist in the ante 2.1.1. Complement system
rior chamber and their dysfunction may be related to TM dysfunction The complement cascade is activated as part of the innate immune
and increased resistance to aqueous outflow, the main cause of increasd response against pathogens or injury, and plays a major homeostatic role
IOP in POAG (Saccà et al., 2016). by clearing damaged cells and cellular debris. The complement cascade
Moreover, a chronic subclinical inflammation has been widely is believed to play multiple roles during different stages of glaucoma
documented on the ocular surface as a result of long-term topical including modulation of the immune response such as cell adhesion,
treatments, and there is a clear correlation between the duration of chemotaxis, phagocytosis or cell lysis (Xu and Chen, 2016). A low-level
treatment and the number of anti-glaucoma drugs, with age and severity of complement activation is maintained under physiological conditions
of glaucoma (Broadway et al., 1994a, 1994b; Baudouin et al., 2010, through the alternative pathway. A gene expression study showed that a
Baudouin et al., 2013). This inflammation may also have a detrimental few genes involved in the classic complement pathway (C1qa, C1qg, C3,
effect on conjunctival and corneal barrier functions and cause activation and C4) and the alternative complement pathway (Complement facteur
of highly immunologically active tissues. It has also been suggested that B and C3) were upregulated in the mouse aging retina, whereas two
if the surface inflammation penetrates deeper into the anterior segment genes involved in the lectin complement pathway (Mannan-binding
it can influence TM dysfunction (Baudouin et al., 2012; Janson et al., lectin-associated serine protease [Masp] 1 and Masp 2) were down
2018). Consequently, glaucoma appears as a disease where inflamma regulated (Chen et al., 2010). A discrete increased deposition of com
tory changes may be present to various extents and with various con plement (C3d) was evidenced by confocal examination in the ganglion
sequences all along the eye structure. cell layer to the inner plexiform layer of the neuroretina, suggesting that
In addition to the pathophysiological interest of understanding the increased complement activation also exists in the neuroretina of aged
role of inflammation in glaucoma and how inflammatory mediators may mice (Chen et al., 2010). Such activation of the complement system may
interact together and possibly with extraocular components (e.g. the be a protective adaptive response to chronic aged-related changes.
central nervous system, the immune or vascular components), modu
lating the local immune response mediated by the glial cells and the 2.1.2. Retinal immune cells
complement system to restore a normal immune homeostasis may be an Glial cells, which include microglia, astrocytes and Müller cells help
attractive therapeutic target in glaucoma (Adornetto et al., 2019). maintain retinal homeostasis (Vecino et al., 2016). They are activated to
2
restore tissue homeostasis and facilitate tissue cleaning and healing caspase-dependent apoptosis of RGC (Calkins, 2012; Cooper et al., 2016,
(Jiang et al., 2020). Microglial cells are resident retinal macrophage-like 2018). Using the DBA2/J mice model, Cooper et al. (2018) demon
cells whose main functions are phagocytosis and elimination of cellular strated that astrocytes remodeling without gliosis preceded optic nerve
debris from damaged cells in the ganglion cell layer, the inner and outer axonopathy. They found that astrocytes in the ONH organize to form a
plexiform, and the inner nuclear layer (Kaur et al., 2015). When acti very well connected network as an early adaptive response to the IOP
vated, ramified quiescent microglial cells become amoeboid with the stress. When disease progresses, the well parallel organisation of astro
ability to proliferate, present antigens, and produce numerous neuro cytes is lost, concurrently with the axonal degeneration.
destructive molecules, inflammatory mediators, including reactive ox Previously, they showed that the pre-degenerative expansion of axon
ygen species (ROS), cytokines, chemokines, prostaglandins, nitric oxide size was accompanied by a retraction of the astrocytes process to the
(NO) and glutamate (Nakamura, 2002). Microglial cells are also the nerves edge, and the frank loss of mitochondria (Cooper et al., 2016).
main sources of retinal complement gene expression in aging retina (Luo However, before axons are lost, they also expand with loss of cytoskel
et al., 2011). They can release numerous neurotrophic factors such as etal integrity as also demonstrated by Tehrani et al. (2014, 2016).
brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor Diminished bioenergetics resources could be a primary inducer of pro
(CNTF), glial cell line-derived neurotrophic factor (GDNF), nerve gression in glaucoma (Li et al., 2015) and the number of mitochondria
growth factor (NGF), neurotrophin-3 (NT3), and basic fibroblast growth could decrease when axon size increases (Cooper et al., 2016). Consis
factor (bFGF) and thus play an important role in neuronal physiology tent results suggesting an early rearrangement of ONH astrocyte pro
and survival (Carwile et al., 1998). Microglial cells also secrete soluble cesses orientation and early loss of gap junctions, and thus loss of
angiogenic factors suggesting a contributing role in the retinal vacula homeostasis in response to chronically elevated IOP was also reported
ture system (Alves et al., 2020). Microglial functions are controlled by using a rat glaucoma model (Johnson et al., 2000; Tehrani et al., 2014).
communication between neurons, astrocytes, and Müller cells. When
well balanced, microglial activation is reversible and does not cause 2.2.2. Early glial cells activation in glaucoma
secondary neuronal degeneration (Nakamura, 2002; Harada et al., Several animal glaucoma models have provided evidence for the
2002). activation and recruitment of microglial cells and astrocytes during
Müller cells are the most abundant glial cells in the retina and span early stage glaucoma prior to RGC loss and morphologically detectable
the entire thickness of the retina (Bringmann et al., 2006). These cells glaucomatous damage to the optic nerve and retina (Naskar et al., 2002;
are responsible for the homeostatic and metabolic support of the sur Bosco et al., 2011; Wang et al., 2014; Sapienza et al., 2016; Johnson
rounding RGCs, including production of adenosine triphosphate (ATP) et al., 2007; Lozano et al., 2019: Oikawa et al., 2020).
and anti-oxidants, glucose metabolism, and ion/substrate exchange In DBA/2 J mice, which is an established model of inherited
(Vohra and Kolko, 2018). Müller cells protect neurons via a release of pigmentary glaucoma, the clustering, activation and migration of
neurotrophic factors, the uptake and degradation of glutamate and the microglial cells was detected in the retinal periphery and in the unmy
secretion of the anti-oxidant glutathione (Bringmann et al., 2009; elinated portion of the ONH several months prior to detectable neuronal
Toft-Kehler et al., 2016, 2017). These cells play a crucial protective role pathology (Bosco et al., 2011). Early microglial activation was also
by preventing accumulation of glycine, gamma amino butyric acid strongly correlated with the severity of ONH degeneration, suggesting
(GABA) and glutamate in the retina (Lebrun-Julien et al., 2009). that neurodegenerative severity could be predicted from early changes
Astrocyte cells line the pores of the lamina cribrosa and blood vessels in microglia (Bosco et al., 2015). The alterations in microglia were
and are thought to play a crucial structural role in secreting extracellular initially detected in the ONH and further progress along the retinal
matrix (ECM) molecules (Schneider and Fuchshofer, 2016). Resting as paremchima overtime (Bosco et al., 2015). Additionally, inhibition of
trocytes function to maintain homeostasis, regulate blood flow, recycle microglial activation in irradiated mice or minocycline-treated mice was
neurotransmitters, maintain synapses, and participate in neurogenesis. shown to protect against neurodegenerative changes in DBA/2 J mice
In the ONH, astrocytes facilitate myelination and myelin maintenance demonstrating that these cells play a major role in glaucoma progression
by clearing extracellular ions and neurotransmitters and by secreting (Bosco et al., 2008, 2012; Wang et al., 2014).
pro-myelinating factors. They are thus critical for retinal signals trans Recently, Tribble et al. (2020) suggested that mitochon
mission to visual structure of the brain (Lundgaard et al., 2014). As drial/metabolic changes rather than inflammatory changes of microglial
trocytes produce anti-inflammatory cytokines, heat shock proteins cells in the ONH may be an early pre-degenerative disease feature in
(HSPs) and neuroprotective factors (BDNF) aiding in neural regenera DBA/2 J mouse glaucoma model. The transcriptomic profile of ONH
tion. They are also the main producers of vascular endothelial growth microglial cells suggests an upregulation of mitochondrial phosphory
factor (VEGF) in response to hypoxia, which plays an important role in lation and of glycolysis/gluconeogenesis in microglial cells suggesting
retinal vascularisation (Russo et al., 2016; Nutma et al., 2020). an increased capacity to metabolise energy from various sources. Genes
Reactive glial responses and para-inflammation represent the initial that regulate the immune surveillance and phagocytosis mediated by the
adaptive reaction of the retina to primary stress stimuli, which can TREM2-TYROBP signaling pathway were downregulated. By contrast,
become detrimental if stress persists or repeats (Pekny and Pekna, there was no change in gene expression of pro-inflammatory mediators,
2014). At extreme levels of activation in response to detrimental tissue unless decreased expression of chemokine C–C ligand (CCL)-5 and
damage and inflammation, Müller cells and astrocytes can cause scar increased expression of transforming growth factor (TGF)-β2, known to
ring, contribute to neurodegeneration, and hinder regenerative pro display an anti-inflammatory and survival signal for microglial cells.
cesses in retinal tissue (Bringmann et al., 2009; Sofroniew, 2009). In the hypertensive rat glaucoma model (unilateral episcleral vein
injection of hypertonic saline), proliferation of various cell types
2.2. Early pathogenic events in glaucoma including astrocytes, microglial cells and oligodendrocytes were shown
to be activated by the elevation of IOP and the optic nerve injury
2.2.1. Early astrocytes remodeling in glaucoma (Johnson et al., 2007). Similarly, Sapienza et al. showed that ocular
As reviewed by Calkins (2012), in POAG, stressors related to age and hypertension (OHT) induced retinal inflammation, tissue macrophage
IOP lead to progressive degeneration of the retinal projection to the activation, retinal astrogliosis, macrogliosis, and mRNA upregulation of
brain. This implies that events distal to the retinal ganglion cell bodies in pro-inflammatory cytokines (monocyte chemoattractant protein
the retina are fundamental for understanding both the progression of [MCP]-1/CCL-2, interleukin (IL)-1β, and tumor necrosis factor
neurodegeneration and ultimate vision loss. Glaucoma progression has [TNF]-α]) (Sapienza et al., 2016) (Fig. 1).
been characterised by early axon expansion and astrocytes migration to Compementary deoxyribonucleic acid (DNA) microarray analysis in
the optic nerve edge, followed by astrogliosis, axon loss through the hypertensive rat glaucoma model showed a dramatic increase in
3
Fig. 1. Elevated IOP induces astrogliosis

and microgliosis in the optic nerve and
superior colliculus. Elevated intraocular
pressure (IOP) over 40 days after episcleral
vein cauterization (EVC) in rat induced
astrogliosis and microgliosis in the retina,
optic nerve and superior colliculus. (A) Di
agram showing the rodent neuronal visual
pathway. Immunofluorescent labeling of
glial fibrillary acidic protein (GFAP) and
ionized calcium binding adaptor molecule 1
(Iba1) in the retina (B), optic nerves (C) su
perior colliculus (D) after episcleral vein
cauterization in rat. Scale bar, 100 μm.
From Sapienza, A. et al., 2016. Bilateral
neuroinflammatory processes in visual
pathways induced by unilateral ocular hy
pertension in the rat. J. Neuroinflammation
13, 44.
gene expression related to cell proliferation and immune response in the was more pronounced in the retro-laminar region, with almost all
ONH (including myelinated and unmeliated segments) (Johnson et al., glial/macrophage cell expression in the pre-laminar and lamina cri
2007). In this model, a minimal exposure to elevated IOP results in an brosa, and oligodendrocyte precursor cells (OPCs) in the retro-laminar
upregulation of a number of genes in the ONH including genes associ space. In this model, microglia and OPCs specific genes were upregu
ated with cell proliferation, inflammation (IL-6), and vascular function, lated while neurons and myelinated oligodendrocytes genes were
and ECM remodeling, consistent with early immune cell responses and down-regulated. In addition, there was no significant cell proliferation
microglial activation but apparently in the absence of a significant in late stage chronic glaucoma, suggesting that microglia proliferation
astrocyte activation in the ONH (Johnson et al., 2011). Recently, it was may be restricted to early-stage glaucoma. On the other hand, enrich
shown that early astrocytes proliferation predominated in the anterior ment and activation of ONH astrocytes in early stage were less promi
(unmyelinated) and transition (partially myelinated) region of the ONH nent, in contrast with the rat hypertensive glaucoma model (Lozano
(Lozano et al., 2019). The early glial proliferative response may be et al., 2019; Sapienza et al., 2016). The transcriptome analysis of the
initiated by the activation of the Jak-Stat signaling pathways which ONH in this feline glaucoma model showed up-regulation of various
up-regulates the generation of IL-6 type molecules (Johnson et al., 2011; pathways in early glaucoma including ribosome, cytokine-cytokine re
Lozano et al., 2019). ceptor interaction, complement coagulation cascades and ECM receptor
Recently, using a feline congenital glaucoma model (ortholog of a interaction pathways. Two signaling pathways were up-regulated the
human primary congenital glaucoma), Oikawa et al. (2020) showed nuclear factor (NF)-κB and MyD88-dependent TLR pathway including
ONH remodeling and functional deficits following the onset of IOP damage-associated molecular patterns (DAMPs) which are endogenous
elevation and prior to axon loss compared with age-matched control ligands of TLRs (Oikawa et al., 2020).
animals. Upregulation of cell proliferation and expression of Using an in vitro model of retinal cells exposed to elevated hydro
inflammatory-related genes was shown in the ONH in early stage. Ac static pressure (EHP), Aires et al. (2020) showed that the content of
cording to the sub-region of glaucomatous ONH, glial cell proliferation exosomes of retinal microglial cells exposed to EHP increased the
4
reactivity of naïve microglial cells including increased production of In contrast, the protective phenotype (M2 phenotype) may be
proinflammatory cytokines (TNF-α and IL-1β), expression of major his maintained by anti-inflammatory cytokines (e.g. IL-5, IL-10) which are
tocompatibility complex class II (MHC-II) molecules, enhanced micro thought to inhibit inflammation, enhance tissue repair and wound
glia motility, phagocytic efficiency, and proliferation (Aires et al., healing, and also to promote RGC survival (Huang et al., 2009). Another
2020). In addition, the exosomes of microglial cells exposed to EHP possible dual phenotype could be the differential expression of TNF
increased neural cell death and increased the ROS production. Intra receptor (TNFR)1 and TNFR2 on glial cells leading to different TNF-α
vitreous injection of exosomes derived from EHP exposed cells were able signaling pathways followed by the formation of pro- or
to induce a sustained activation of retinal microglia, mediated cell anti-inflammatory mediators, respectively. In response to stress stimuli,
death, and impacted RGC number in C57BL/6 J mice. Exosomes are astrocytes may express the TNFR1 phenotype and release a number of
nanometer-sized vesicles that are released by cells in a controlled pro-inflammatory and immune mediators linked to NF-κB activation
fashion and mediate a plethora of extra- and intercellular activities (Tezel et al., 2012). By contrast, activation of TNFR2 in microglia may
including cell-cell communication, immune modulation, extracellular promote induction of anti-inflammatory pathways like those driven by
matrix turnover, stem cell division/differentiation, neovascularization granulocyte colony-stimulating factor (G-CSF), adrenomedullin and
and cellular waste removal (Klingeborn et al., 2017). Thus, this model IL-10 (Veroni et al., 2010). Yet, the oligodendrocyte and RGC death
suggests that exosomes derived from retinal microglia may have an induced by TNF-α was also shown to be mediated by the TNFR2 re
autocrine function in the propagation of the inflammatory signal in ceptors in a model of angle closure IOP glaucoma thus inconsistent with
conditions of elevated pressure, contributing to retinal degeneration in the TNFR2 signaling of cell survival (Nakazawa et al., 2006).
glaucomatous conditions (Aires et al., 2020). In addition, the expression of membrane CX3C chemokine (fractal
kine) receptor 1 (CX3CR1) seems to play a role, as its deficiency has been
2.3. Glial cells phenotypes shown to increase microglial neurotoxicity in an experimental mouse
glaucoma model with transient IOP elevation (Wang et al., 2014).
A growing field of glaucoma research has focused on understanding Similarly, another experimental study in DBA/2 J mice has suggested a
whether glial cells exert a protective function via the production of protective role of fractalkine against infiltration of CC chemokine re
neurotrophic factors or contribute to neuronal death by producing toxic ceptor (CCR) 2+ macrophages in the retina and in the protection against
inflammatory factors. Retinal glia cell response in glaucoma may also axonal transport dysfunction, through enhanced nitric oxide synthase
change as the disease progresses from early to advanced injury (Nickells, (NOS)-2 expression in myeloid cells (Breen et al., 2016).
2007; Johnson and Morrison, 2009). Similarly, as demonstrated in mouse brain, a dual phenotype, i.e.
As an intermediate between basal/normal and inflammatory states, neurotoxic (A1) upregulating inflammatory mediators or neuro
para-inflammation can induce different degrees of glial cells activation protective (A2) promoting healing, has been characterized for astrocytes
(Xu et al., 2009). As shown in the mouse central nervous system, retinal (Liddelow and Barres, 2015; Liddelow et al., 2017). A1 reactive astro
microglial cells and astrocytes are very heterogeneous cell populations cytes were shown to lose many normal astrocyte functions including
characterised by various metabolic states and degrees of activation synapses formation in RGCs and phagocytic capacity (Liddelow et al.,
(Hammond et al., 2019). Microglial cells are also characterized by 2017).
transcriptionally distinct states as demonstrated in brain mice (Ham
mond et al., 2019). It is still not known if these states are transient or 2.4. Complement system activation
represent terminal differentiation subsets of microglia. It was also sug
gested that some microglial cell populations may be primed by As part of the innate response, complement pathways are also
age-related changes and neurodegenerative disease leading to a more intrinsically linked with the process of glial activation in the patho
vigorous uncontrolled maladaptive response to inflammatory challenges genesis of glaucomatous damage within the retina (Soto and Howell,
contributing to disease progression (Perry and Teeling, 2013). 2014). Increased protein expression of C1q, the initiating protein of the
The mechanisms that cause the progression from a protective in classical complement cascade, in the retina has been reported in animal
flammatory response to chronic neurotoxic inflammation in glaucoma glaucoma models, including the monkey, and in some human glau
are largely unknown (Zeng and Shi, 2018). It seems that the microglial comatous retinal specimens obtained after enucleation (Kuehn et al.,
responses to injury become altered with aging and aged microglia may 2006; Stasi et al., 2006; Stevens et al., 2007; Tezel et al., 2010; Williams
be less capable of maintaining homeostasis of the immune environment et al., 2016). Uncontrolled complement activation in glaucoma is
resulting in microglial inflammation and neurotoxic phenotype (Ma and believed to contribute to the progression of degenerative injury to RGCs,
Wong, 2016; Chen et al., 2019). Under physiological conditions, their synapses, and axons. The increased levels of expression of C1q may
endogenous factors downregulate inflammation and provide a negative be initially induced by the elevated IOP before the loss of RGCs, and then
feedback that switches off the inflammatory response and prevents parallel the RGC loss (Kuehn et al., 2006; Stasi et al., 2006; Williams
inflammatory-mediated damage. Sun et al. demonstrated that mild IOP et al., 2016).
elevation led to a reversible activation of astrocytes in mice (Sun et al., Components of the C1 complex may be upregulated in multiple cell
2013). In contrast, astrocytes exposed to proinflammatory injury in the types in the retina and ONH during early stages of glaucoma, particu
central nervous system (CNS) exhibited a phenotype that led to direct larly myeloid-derived cells and RGCs (Howell et al., 2011, 2014; Wil
damage of the axons with ROS release, pro-inflammatory cytokines, and liams et al., 2016). It was also suggested that C1q might be rapidly
modulation of the ECM, forming a scar opposed to axon regeneration upregulated within microglia and neurons concurrently with the
(Zamanian et al., 2012). As suggested, prolonged exposure to glau appearance of reactive astrocytes and/or Müller cells (Stasi et al., 2006;
comatous stress may shift the balance from a physiological process to Stevens et al., 2007).
ward a pro-inflammatory neurodegenerative process (Tezel, 2013). The The role of complement system in neurodegenerative disease is not
glial cell phenotype may depend on the disease stage and severity as clear since these molecules may have beneficial or damaging effects (Xu
observed in other neurodegenerative diseases (Tang and Le, 2016; Seitz and Chen, 2016). Activation of C1qa was shown to promote synapse
et al., 2013; Zeng and Shi, 2018; Wie et al., 2019). opsonisation and phagocytosis by microglial cells in animal models,
The cytotoxic phenotype (M1 phenotype) in microglia may promote which could explain early synapse loss and dendritic atrophy before
the activation of NF-κB, a transcriptional factor which generates high axon and soma loss in animal models (Williams et al., 2016). One
levels of pro-inflammatory cytokines promoting tissue inflammation, postulated mechanism may be the aberrant reactivation of synapses
oxidative metabolites and RGC death (Dvoriantchikova et al., 2009; elimination mediated by the classical complement cascade leading to
Yang et al., 2011). early synapse loss associated with glaucoma (Stevens et al., 2007; Rosen
5
and Stevens, 2010). Previous animal studies have found that HSP27 and HSP60 immu
In addition, membrane attack complex has been shown to be formed nisation in rats induces a rapid and transient retinal T cell infiltration
in the RGC layer in both human and rat glaucoma (Kuehn et al., 2006). associated with microglial activation and RGC apoptosis via the release
In animal models of glaucoma, inhibition of C1q has been shown to of the proapoptotic cytokine FasL, a member of the TNF-α family (Wax
reduce RGCs loss, and induction of C5 to aggravate the ONH degener et al., 2008).
ation confirming the link between classical complement activation and Increased expression of MHC class II antigens by activated glial cells
the development of glaucoma. By contrast, upregulation of C3 by as in glaucomatous retina and ONH may therefore promote T-cell activa
trocytes in the ONH may be protective from glaucomatous damages tion, suggesting an innate/adaptive interplay in glaucoma (Luo et al.,
(Howell et al., 2013; Williams et al., 2016; Harder et al., 2017). The 2010).
apparent paradoxical role of C1q and C3 complement components may On the other hand, elimination of T cells by apoptosis is considered
be explained by their generation through different independent path as an essential protective mechanism to prevent inflammation in
ways, as suggested for autoimmune disease (Scott and Botto, 2016). immune-privileged tissue (Wax et al., 2008). Such protective role of
In addition, a trend toward downregulation of the complement factor inflammation signaling was also evidenced in animal studies. Experi
H expression was observed in human retina of glaucomatous donors mental intraocular inflammation in rat was shown to stimulate macro
(Tezel et al., 2010). Such an alteration suggests increased vulnerability phage infiltration, Müller cell activation, and expression of growth
of RGCs to complement-mediated lysis in glaucoma. factors in RGC, leading to enhanced RGC survival and axon regeneration
in the optic nerve (Leon et al., 2000; Yin et al., 2009).
2.5. Fas ligand signaling
2.7. Inflammatory findings from glaucomatous human tissues
The constitutive expression of FasL, a transmembrane protein of the
TNF family with the capacity to induce apoptosis in Fas receptor positive Studies using animal models of glaucoma can not predict what’s
(Fas+) cells, including RGCs in the retina, is believed to maintain im happen in human primary open glaucoma, which is a multifactorial
mune privilege in part by inducing apoptosis of infiltration T cells. disease. Nevertheless, histological studies in human suggest the activa
Studies conducted by Ksander and coworkers showed that FasL when tion of glial cells and the resulting intense inflammatory reaction asso
expressed as a membrane-bound protein (mFasL) in microglial cells was ciated with glaucomatous neural damage (Yuan and Neufeld, 2001).
pro-apoptotic and pro-inflammatory, and when elevated and released as Compared to normal specimens, ONH specimens from advanced glau
a soluble isoform (sFasL), it was non-apoptotic, and non-inflammatory coma of human donors have shown a proliferation of microglial cells in
(Krishnan et al., 2019). Increased expression of membrane FasL has all regions of the ONH, including the lamina cribrosa, as indicated by the
been detected in microglial cells in the chronic hypertensive rat glau elevated expression of proliferating cell nuclear antigen (PCNA)-positive
coma model (Ju et al., 2006), and cleavage of the membrane FasL was microglial cells (Yuan and Neufeld, 2001). The expression of immuno
considered as an important mechanism protecting retinal tissue from modulating (TGF-β2, prostaglandin E2 [PGE2]) and pro-inflammatory
extensive degeneration (Gregory et al., 2011). Interestingly, they found mediators (TNF-α, inducible nitric oxide synthase [iNOS]) seems to be
that induction of soluble FasL correlated with inhibition of glial acti upregulated, as well as the expression of various metalloproteinases
vation, reduced production of TNF-α, and decreased apoptosis of RGCs (MMPs) (MMP-1, MMP-2, MMP-3, MMP-14), and tissue-inhibitor met
and loss of axons, even in the presence of elevated IOP (Krishnan et al., alloproteinases (TIMPs) (TIMP-1, and -2), suggesting an intense in
2016). flammatory and remodeling reaction in the glaucomatous ONH. More
recently, increased protein levels of pro-inflammatory cytokines (TNF-α,
2.6. Immune cells infiltration IL-1β, IL-6, IL-8, and interferon [IFN]-γ) in human glaucomatous retinal
tissue have been reported (Gramlich et al., 2013). ONH specimens of
Glaucoma appears to be a neuroinflammatory disease with damages post-mortem glaucomatous eyes were also characterised by abundant
coordinated through dysfunctional RGCs, reactive glial cells and infil glial fibrillary acidic protein (GFAP)-positive astrocytes, which
tration of circulating immune cells. co-localised with high levels of human leukocyte antigen class II anti
There is a growing consensus that sustained and excessive glial re gens (HLA-DR) (Yang et al., 2001; Tezel et al., 2003). Cell adhesion
actions lead to extended immune responses, including adaptive immu proteins (e.g. integrins) have also been found to be overexpressed in
nity, characterized by T-cell infiltration, contributing to progressive glaucomatous astrocytes, indicating that these cells could promote the
nerve damage in glaucoma (Jiang et al., 2020). adhesion and migration of immune cells to damaged regions of the ONH
Studies have suggested that the immune adaptive response may be (Soto et al., 2014). In human glaucomatous ONHs, astrocytes also
associated with RGC death and glaucomatous retinal degeneration expressed high levels of TNF-α and TNFR, which parallels the progres
(Tezel and Wax, 2000; Wax et al., 2008). In this context, there is evi sion of ONHretina from glaucomatous donors showed signs of chronic
dence to suggest that the retinal blood barrier is dysfunctional in pa oxidative stress, as revealed by the increased levels of oxidative
tients with glaucoma, and that infiltration of immune cells, including by-products immunolabeling in glaucomatous retina compared to con
monocytes and lymphocytes, occurs in the retina of patients with trol donors (Tezel, 2006). Proteomic analyses showed increased
glaucoma (Gramlich et al., 2013; Tezel, 2009). Monocyte infiltration has expression of TLRs including TLR-2, -3, and -4 which localized on retinal
been shown to be coincident with the onset of glaucoma in the DBA/2 J microglia and astrocytes (Luo et al., 2010). Various inflammasome
mouse, while irradiated DBA/2 J mice lacking infiltrating monocytes, components including NOD-like receptor pyrin (NLRP) 3, caspase 1, and
did not develop retinal neurodegeneration (Howell et al., 2012). Inhi caspase 8 are also increased in glaucomatous compared with normal
bition of monocyte-like cell extravasation clearly protected from neu eyes (Yang et al., 2011).
rodegeneration in DBA/2 J glaucoma (Williams et al., 2019). TLRs are the first line of host defence mechanisms against pathogens
Consistently, macrophages have been detected in axon bundles of and non pathogens stress stimuli. They are known to induce a rapid
post-mortem ONH of patients with mild or severe glaucoma (Margeta innate response by recruiting adaptor proteins and activating the tran
et al., 2018). Increased retinal deposition of immunoglobulin G (IgG) scription factor NF-κB, thereby leading to the expression of pro-
autoantibodies has been detected in eyes of glaucoma patients, and inflammatory cytokines. TLRs induce transcriptional activation of pro-
infiltration of T and B lymphocytes into the retina has also been detected IL-1β, which is proteolytically processed via inflammasome activation
(Gramlich et al., 2013). It is possible that activated T cells may be (Netea et al., 2008; Schroder and Tschopp, 2010). In vitro experiments
directly cytotoxic to RGCs and induce RGC apoptosis mainly through showed that oxidative stress and heat shock proteins could activate glial
death receptor-mediated signaling. cells via the TLRs signaling. Both TLRs and inflammasome seem to be
6
dysregulated in glaucoma. Animal models showed upregulation of the 3. Neuro inflammatory mechanisms in glaucoma
TLR signaling in early glaucoma (Oikawa et al., 2020).
These findings are therefore in accordance with the retinal inflam A number of molecular and signaling pathways that are key regu
mation observed in animal models of glaucoma. lators of neuroinflammation in both human and animal models have
been proposed in the etiology of glaucoma (Danford et al., 2017). These
2.8. Neuroinflammation along the visual pathways mechanisms are complex and involve a close interaction between glial
cells, immune cells, endothelial cells and RGC through autocrine/para
Several studies on glaucomatous neuropathy strongly suggest that crine pathways. One hypothesis is the chronic mechanical and/or
axon impairment spreads through the optic nerve to the posterior visual vascular stress at the ONH and retina, leading to a persistent maladap
pathways of the CNS (Gupta and Yucel, 2007; Yucel and Gupta, 2008). tive inflammatory phenotype in the context of increased oxidative stress
Changes in the expression patterns of several synaptic plasticity markers and aging/senescence, associated with a loss of neuroprotective and
in the lateral geniculate nucleus (LGN) have been observed in patients or remodeling functions of glial cells, release of apoptotic signals, RGC
primate models of glaucoma, demonstrating a lower functional con degeneration, blood retinal barrier disruption, and ONH tissue remod
nectivity (Lam et al., 2003). Post-mortem histopathologic analysis of eling (Almasieh et al., 2012).
brain sections of patients with advanced glaucoma indicated lower
neuron density in the LGN (Weber et al., 2000). This lower connectivity 3.1. Ischemia/hypoxia
was correlated with LGN degeneration and shrinkage of the cellular
body, causing loss of neurons and reduced metabolic activity, which Hypoxia is believed to play an important role in initiating and
lead to visual alteration (Yucel et al., 2001; Sasaoka et al., 2008). The driving retinal damage in glaucoma. According to the vascular hy
shrinkage of the cellular body and loss of neurons has also been docu pothesis of glaucoma, RGC axons traversing the ONH, undergo oxygen
mented in the visual cortex of glaucoma patients (Chaturvedi et al., and nutrient insufficiency resulting from compromised local blood flow,
1993; Gupta et al., 2006). In murine models of OHT (episcleral vein which ultimately leads to their degeneration (Chidlow et al., 2017). The
perfusion with saline solution or DBA/2 J), the shrinkage and dendritic unstable ocular blood flow produced by chronically elevated and/or
loss of neurons has also been detected in the superior colliculus, the oscillating IOP, together with possible vascular dysfunction (e.g.
major optic nerve fibre relay in the rodent brain (Liu et al., 2014; decreased perfusion pressure, autoregulation deficit or vasospasm) can
Dengler-Crish et al., 2014). In these ocular hypertension models, an lead to repeated hypoperfusion and chronic oxidative stress associated
increase in the number of GFAP-positive astrocytes throughout the su with inflammation (Flammer et al., 2002; Mozaffarieh et al., 2008). The
perficial layers of the contralateral superior colliculus could be detected resulting ischemic damage and hypoxia can initiate acute or prolonged
(Zhang et al., 2009; Dekeyster et al., 2015). Similarly in non-human inflammatory reactions characterised by the generation of
primates, astrogliosis has been reported in the LGN and visual cortex pro-inflammatory mediators and infiltration of various inflammatory
following IOP increase induced by photocoagulation of the trabeculum cells into the ischemic tissue (Vohra et al., 2013). Increased expression
(Lam et al., 2009). of hypoxia inducible factor 1α (HIF-1α) has been found in post-mortem
By contrast, Crish et al. (2013) showed using DBA/2 J mice, that human glaucomatous retinas. The location of increased HIF-1α in the
focal deficits in anterograde axonal transport from retina to the superior retina of glaucomatous eyes concurred with the location of visual field
colliculus induced a concurrent elevation of BDNF, especially in hy defects, supporting the presence of hypoxia in the retina and ONH of
pertrophic astrocytes, that is spatially coincident with retinotropic glaucomatous patients (Tezel and Wax, 2004). In a rat model of hy
location of transport loss, suggesting a local intrinsic protective mech pertensive glaucoma, high levels of HIF-1α were present specifically in
anism to slow loss of retino-collicular synapses. astrocytes and Müller cells (Ergorul et al., 2010). HIF-1α has also been
Microglial activation has been also described in relation to degen found to induce the production of VEGF and NOS, which may be
erating neurons in glaucoma. In a preclinical model of glaucoma (ob responsible for blood-retinal barrier disruption in glaucoma (Kaur et al.,
tained by unilateral episcleral vein cauterisations in the rat), Sapienza 2008). Increased expression of HIF-α in isolated retina has also been
et al. demonstrated the presence of inflammation along the visual associated with up-regulation of p53 and pro-apoptotic caspases (Tezel,
pathways beyond the back of the eye (Sapienza et al., 2016) (Fig. 1). 2006). The expression of TNF-α and IL-1β in primary cultures of
RGC death was shown in the cauterised eye and, interestingly, in the microglial cells was shown to be dramatically increased in response to
contralateral eye as well. Thus, retinal inflammation characterised by hypoxic exposure, and conditioned medium derived from hypoxic
tissue macrophage activation and elevated pro-inflammatory cytokines microglia enhanced apoptosis, which was significantly decreased when
was present bilaterally, although at a lower level in the normotensive cells were pre-treated with anti-TNF-α/IL-1β antibodies (Sivakumar
eye. It was suggested that retinal neuroinflammation was transmitted et al., 2011). Recruitment of microglia was also observed in the RGC
along the optic nerve via the superior colliculus. Inflammatory media layer in the rat retinas subjected to hypoxia (Kaur et al., 2015).
tors in one eye could be activated and circulate along RGC fibres and Furthermore, hypoxia produced mitochondrial damage in retinal cells
induce inflammation in the two superior colliculus, which may activate including RGCs and Müller cells, leading to abnormal accumulation of
inflammation in the other eye by retrograde transport via RGC fibres glutamate, activation of N-methyl-D-aspartate (NMDA) and
(Sapienza et al., 2016). In this model, retinal inflammation, tissue alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
macrophage activation and elevated levels of pro-inflammatory cyto receptors, increased intracellular calcium influx, caspase signaling and
kines were present bilaterally (normotensive and hypertensive eyes). RGC death (Harris et al., 2005).
These findings raise important hypotheses on the possible risk of diffu
sion of IOP-related RGC degeneration in unilateral or asymmetrical 3.2. Endothelins (ETs)
glaucoma to the visual pathways, both in ipsilateral and contralateral
modes. If these hypotheses are confirmed in the future using more ETs are other vascular factors closely related to glial cell activation,
sensitive neuroimaging technologies, clinicians should be warned about ischemia and blood-retinal barrier disruption. The ET receptors have
possible bilateralisation of the disease and the need for careful moni been shown to mediate RGC loss and ONH degeneration (Howell et al.,
toring of the contralateral eye, with the potential for more aggressive 2011; Minton et al., 2012). ET-1 is a potent vasoconstrictor produced by
interventions. vascular endothelial cells, but also by microglia/macrophages that play
a role in local vascular tone (Howell et al., 2011; Kowalczyk et al.,
2015). Increased plasma levels of ET-1 have been found in POAG pa
tients and this may be linked to vasoconstriction, decreased ocular blood
7
flow and ischemia/hypoxia (Li et al., 2016). Acute intraocular injection in glial dysfunction. Chronic oxidative stress is considered as the main
of ET-1 in rats has been shown to increase GFAP expression in Müller initial trigger of retinal para-inflammation in aging retina, and dysre
cells, indicating glial cell hyperactivity and RGC death (Lau et al., 2006). gulated para-inflammation in glaucoma as reviewed by Xu et al. (2009).
ET-1 has also been shown to induce proliferation of human ONH as ROS also play an essential role as signaling molecules driving gene
trocytes in culture through ET (A/B) receptor activation (Prasanna et al., transcriptions involved in inflammation. Oxidative stress activates the
2003). In DBA/2 J mice, ET-2 was shown to be produced in astrocytes as redox-sensitive transcription factor NF-κB, which is known to regulate
well as in microglia/macrophages in ONH at an early stage before retinal the expression of inflammatory molecules (including IL-6, TNF-α, iNOS,
damage (Howell et al., 2014). Both ETA and ETB receptors were upre intercellular adhesion molecule [ICAM] 1, MMP9) and apoptosis-
gulated during the early stage of retinal neurodegeneration (ETA inhibiting factors, such as B-cell lymphoma 2 (Bcl-2) (Kabe et al.,
expression was present in endothelial cells and ETB was more specif 2005; Harari and Liao, 2010). Inactivation of NF-κB in transgenic mice
ically found in astrocytes in the ONH). Oral administration of an ETA/B astrocytes was found to promote survival of retinal neurons after
receptor antagonist was shown to lead to a partial inhibition of RGC ischemic injury (Dvoriantchikova et al., 2009). On the other hand, there
death (Howell et al., 2014). Intravitreal injection of ET-2 peptide was is some evidence for an inhibition of the anti-oxidative Nrf2 pathway in
also shown to cause RGC axon damage (Howell et al., 2011), and reverse glaucoma (Ahmed et al., 2017; Wang et al., 2020). This activation of
the inhibition of monocyte infiltration (Howell et al., 2012). In an ocular Nrf2 was shown to inhibit the NF-kB pro-inflammatory pathways and to
hypertensive rat model, elevated IOP resulted in overexpression of ETA promote neuronal survival in neurodegeneration and acute nerve
and ETB in the retina and was associated with cell death (McGrady et al., damage (Xiong et al., 2015).
2017). Finally, Wang et al. reported upregulation of ETB expression in
ONH astrocytes in an ET-1-induced chronic optic neuropathy, causing 3.4. Mitochondrial dysfunction
RGC loss (Wang et al., 2009).
The retina is one of the most energy and oxygen demanding tissues in
3.3. Chronic oxidative stress the body (Lee, 2011). In this context, mitochondria are essential for
retinal homeostasis, and substantial evidence has shown that retinal
The retina is constantly exposed to ROS due to intense mitochondrial damage is triggered and perpetuated by mitochondrial dysfunction.
activity and oxidative stress is considered as an important pathogenic Mitochondria produce ROS as a by-product of electron leak along the
risk factor in glaucoma (Nita and Grzybowski, 2016). Oxidative stress electron transport chain during cellular respiration (Murphy, 2009).
reflects an imbalance between the production of ROS generated by the This activity is essential to maintain the energy requirements for
oxygen consumption during mitochondrial respiration and antioxidant neuronal function, and RGCs have an absolute requirement for optimal
defences, in which oxidative processes exceed antioxidant systems mitochondrial function to maintain survival (Osborne et al., 2008).
(Chrysostomou et al., 2013; Pinazo-Durán et al., 2015). The excess of Mitochondrial activity may be impaired by ischemia/hypoxia or by
ROS generation is normally counteracted by protective antioxidant oxidative stress most likely associated with glaucoma. A lack of nutrients
mechanisms including antioxidant enzymes such as superoxide dis or oxygen can not only result in bioenergetically compromised RGC
mutase, catalase, and glutathione peroxidase, vitamins and vitamin-like axons, but can also dramatically increase ROS production, which leads
molecules (polyphenols). If not rapidly recycled, the unstable oxygen to further oxidative stress and retinal damage (Chrysostomou et al.,
species can attack lipid membranes, cellular proteins and nucleic acids, 2013; Eells, 2019; Kolko, 2017). Dysfunctional mitochondria also
leading to apoptosis and cell death. Antioxydant enzymes expression is release multiple DAMPs, such as ATP, ROS, and mtDNA, which activate
tightly regulated through the nuclear factor erythroid 2-related factor 2 the NLRP3 inflammasome. This triggers the proteolytic maturation of
(Nrf2) pathway (Nakagami, 2016), which was shown to be impaired in proinflammatory cytokine precursors, such as IL-1β, and leads to the
aging (Zhang et al., 2015). Overall, senescent cells are associated with activation of the NF-κB pathway (Martinon, 2010).
high level of intracellular ROS and the oxidative stress increase with age Under conditions of increased IOP and/or unstable oxygen tension,
while the ability to respond to the oxidative stress decline with age the simultaneous production of NO in astrocytes and of superoxide in the
(Pinazo-Durán et al., 2014; Zhang et al., 2015). In aging animal, mitochondria of neuronal cells lead to the production of peroxynitrate
para-inflammation was associated with an accumulation of oxidative (ONOO-) (Neufeld et al., 1997; Mozaffarieh et al., 2008; Konieczka et al.,
stress products including oxidized proteins and lipids, oxidized lipo 2014). Peroxinitrate has strong oxidising properties against a wide va
proteins and metabolic products e.g. the advanced glycation end prod riety of molecules, including DNA and proteins, leading to RGC death. In
ucts (AGEs) (Xu et al., 2009). addition, oxidative stress may alter cycling of glutamate/glutamine,
ROS production and oxidative retinal damage and imbalance be leading to the accumulation of neurotoxic levels of glutamate (Atlante
tween pro-oxidative and antioxidant capacity may be crucial in early et al., 2001; Toft-Kehler et al., 2016) and to Müller cell dysfunction
retinal injury. Glaucomatous ONH astrocytes compared to normal ONH during starvation, potentially causing impaired glutamate uptake and
astrocytes have lower basal levels of reduced glutathion, which may excitotoxicity (Toft-Kehler et al., 2016).
imply a compromised oxidation-reduction system or a reduced antiox Recently, it was confirmed that mitochondrial dysfunction was an
idant response in the glaucomatous optic nerve (Malone and Hernandez, early driver of neuronal dysfunction, before detectable degeneration in
2007). As reviewed by Nita and Grzybowski (2016), oxidative stress DBA/2 J mice (Williams et al., 2017a). Retinal levels of nicotinamide
produced by elevated IOP and/or hypoxia can have detrimental effect adenine dinucleotide (NAD+) were decreased in aging animals, rending
resulting in glaucomatous optic nerve atrophy and optic disc cupping neurons vulnerable to disease-related insults. The main function of NAD
enlargement. In glaucoma, oxidative stress produces oxidative mito as a redox cofactor consists in providing electrons from oxidized nutri
chondrial DNA (mtDNA) damage leading to apoptosis of RGCs (Chrys ents to the mitochondrial respiratory chain complex I, thus sustaining
ostomou et al., 2013) and was shown to impair basal cytoprotective ATP production. Nicotinamide treatment and gene therapy to enhance
autophagy. Oxidative stress also induced ECM remodeling through the NAD producing enzymes were shown to be neuroprotective against
MMPs activation. Oxidative stress also alters the glutamate/glutamine glaucoma in this model. This is consistent with the nicotinamide defi
cycling, leading to the accumulation of neurotoxic levels of glutamate. ciency in POAG (Kouassi Nzoughet et al., 2019).
On the other hand, intracellular and extracellular accumulation of
advanced glycation end products (AGEs) is increased as well as TNF-α 3.5. Glutamate
and NO) secretion by glial cells. In addition, ROS can scavenge NO
radicals and thus increase the vascular tone and impair the ocular blood One protective function of astrocytes and Müller cells is the regula
flow, leading to RGCs apoptosis. There is some evidence for a role of ROS tion of glutamate homeostasis. Accumulation of glutamate is the result
8
of a number of insults, including inappropriate electrical activity, TNFR1 activation while preserving TNFR2-mediated signaling (Cueva
ischemia/reperfusion injury and neurotrophin deprivation. This may Vargas et al., 2015). It was suggested that TNF-α acts as an important
initiate the death of neurons containing ionotropic glutamate (NMDA) regulatory cytokine with differential signaling through the two distinct
receptors (Harris et al., 2005). Activation of NMDA receptors on RGC TNFRs that determine its contribution to degenerative or regenerative
induces the influx of calcium and the generation of free radicals, leading processes. Therefore, depending on the type and stage of glaucoma,
to cell death. It has been suggested that Müller cells may increase RGC environmental/external factors, cellular composition of the affected
susceptibility to stress signals in response to elevated IOP, thereby tissue and intracellular availability of TNFR signaling components,
contributing to disease progression (Bringmann et al., 2009). In support TNF-α may function to aggravate or ameliorate the disease (Marchetti
of this, it has been shown that Müller cells have a reduced ability to et al., 2004).
regulate glutamate homeostasis upon release of TNF-α and other in
flammatory molecules (Vohra et al., 2013; Toft-Kehler et al., 2017; De 3.7. Metalloproteinases
Groef et al., 2015).
There is evidence to suggest a close association between inflamma
3.6. Tumour necrosis factor alpha tion and ECM remodeling in the ONH. Pathological conditions in glau
coma may be due to a disordered deposition of elastic and collagen
TNF-α is found in high levels in the retina and ONH of glaucoma fibres and a typical, pronounced thickening of the connective tissue
patients and appears to play a key role in the regulation of neuro septae that surround the nerve fibres in the lamina cribrosa (Schneider
inflammation (Yuan and Neufeld, 2001; Tezel et al., 2001; Gramlich and Fuchshofer, 2016). Increased elastin expression by astrocytes in
et al., 2013). This cytokine is primarily produced by glial cells, including response to elevated IOP has been documented in the lamina cribrosa
microglia, astrocytes, and Müller cells, and its production seems to be (Pena et al., 2001). The regulation of ECM deposition is normally based
upregulated in glaucoma in response to vascular (ischaemic) or oxida on balanced synthesis and degradation of ECM. It has been speculated
tive stress as previously described (Tezel et al., 2001; Lebrun-Julien that the remodeling of the ONH in glaucoma involves an impaired
et al., 2009; Sivakumar et al., 2011). In the rat hypertensive glaucoma astrocyte response and changes in ECM composition and distribution
model, increased IOP resulted in a dramatic increase in TNF-α levels under the influence of MMPs.
produced by microglial cells around the ONH within a few days, asso MMPs belong to a superfamily of structurally similar proteolytic
ciated with axonal degeneration and a 38% loss of RGCs after several enzymes that cleave ECM components including collagens (MMP-1,
weeks (Roh et al., 2012). Similarly, Cueva Vargas et al. showed that MMP-8, and MMP-13), gelatin (MMP-2, MMP-9) and proteoglycans
TNF-α was upregulated by Müller cells and microglia/macrophages soon (MMP-3, MMP-10, and MMP-11). Under normal conditions, astrocytes
after induction of ocular hypertension (Cueva Vargas et al., 2015). are thought to maintain low MMP activity by high constitutive expres
TNF-α may affect RGC survival through different pathways, including sion of TIMPs (Hernandez, 2000). In contrast, there is evidence of
the activation of NOS expression and NO production (Yuan and Neufeld, abnormally increased production of MMPs and TIMPs by activated as
2000), mitochondrial dysfunction (Kaur et al., 2013), modulation of trocytes in the ONH of glaucoma patients (Agapova et al., 2001).
NMDA and AMPA in Müller cells (Lebrun-Julien et al., 2009; Cueva Pro-inflammatory cytokines (IL-1, IL-8, and TNF-α) are known to upre
Vargas et al., 2015), induction of membrane FasL expression on retinal gulate MMPs expression, resulting in elastin and collagen deposition in
microglia and/or infiltrating macrophages (Krishnan et al., 2016), the surrounding tissues. Hence, changes in MMPs and TIMPs appear to
modulation of tissue remodeling via the synthesis and secretion of MMPs be closely related to the inflammatory responses. Treatment of human
(including MMP-9) (Shubayev et al., 2006), and stimulation of ET-1 ONH astrocytes with the anti-inflammatory TGF-β2 has been shown to
synthesis in several ocular cell types, including ONH astrocytes (Desai result in a shift towards the inhibitory mechanisms of MMP activity due
et al., 2004). to elevated TIMP expression (Neumann et al., 2008).
Some contradictory studies have also shown that TNF-α released by In addition to collagenase proteolysis, MMPs may cleave other sub
activated microglia causes astrocytes to produce neuroprotective factors strates, such as inflammatory cytokines from their inactivated to active
in response to relatively mild hypertensive glaucomatous injury (Lee forms. In this context, experiments in MMP-2 deficient mice showed that
et al., 2014). TNF-α is involved in a complex interplay between this attenuated the loss of RGC induced by intravitreal administration of
pro-inflammatory, pro-apoptotic, and pro-survival pathways mediated NMDA, which was associated with a marked reduction in soluble TNF-α.
by two distinct types of receptors TNFR1 and TNFR2 (Tezel, 2008; Orti- Some have postulated that MMP-2 could cleave a transmembrane pre
Casañ et al., 2019). Mac Nair et al. have shown that RGC loss induced by cursor of TNF-α from membrane glial cells and release soluble, biolog
optic nerve crush in mice was attenuated by the pre-injection of intra ically active TNF-α from the cell membrane (De Groef et al., 2015).
ocular TNF-α, suggesting that it may have a protective role early in the
RGC death process (Mac Nair et al., 2014). This effect may be mediated 4. Inflammation and trabecular meshwork in glaucoma
by TNFR2, which is expressed by microglial cells and when activated
leads to the production of anti-inflammatory cytokines such as G-CSF Upstream of ONH degeneration and RGC loss characteristic of
and IL-10 (Veroni et al., 2010). Opposite effect of TNFR2 receptor glaucoma neuropathy, aqueous humour (AH) outflow resistance and
signaling was found by Nakazawa et al. using an angle-closure hyper elevated IOP are key features of POAG and constitute the most docu
tensive model of glaucoma (Nakazawa et al., 2006). mented risk factor. Increased resistance to outflow results from a pro
Conversely, upon binding to TNFR1 receptors on the RGCs, soluble gressive dysfunction of the remodeling of TM cells and the imbalance
TNF-α induces apoptosis, via activation of the caspase (caspase 8) between the rate of ECM synthesis and breakdown, leading to increased
signaling cascade, loss of mitochondrial membrane potential and gen ECM deposition in aqueous outflow pathways (De Groef et al., 2013).
eration of ROS (De Groef et al., 2015). These processes are consistent The precise pathophysiological mechanisms involved in the outflow
with the high level of TNFR1 in inner retinal layers of glaucomatous eyes resistance are not fully understood. IOP is maintained due to the balance
(Yan et al., 2000; Yuan and Neufeld, 2001; Tezel et al., 2001) and the between production of AH by the ciliary processes and hydrodynamic
significant decrease in RGC death due to neutralisation of TNF effects resistance to its outflow through the conventional outflow pathway
with anti-TNF-α antibodies (Tezel and Wax, 2000). In addition, inhibi comprising the TM and Schlemm’s canal (SC).
tion of TNF-α activity, by a soluble TNF-α receptor antagonist, inhibited
microglial response and prevented axonal degeneration and loss of RGCs 4.1. Structure and function of the trabecular meshwork
in a rat model of hypertensive glaucoma (Roh et al., 2012). Another
study showed that blocking TNF-α minimised the detrimental effect of The TM is a porous structure located between the iris and the cornea
9
innermost surface in the iridocorneal angle. The TM is composed of a and MCP-1) under resting conditions, which supports other observations
complex elastic network of connective tissue beams and sheets or that monocytes, presumably under the influence of chemotactic signals,
lamellae covered by TM cells. TM cells have both medodermal and circulate through the TM in the normal state (Shifera et al., 2010).
ectodermal origins, and behave like endothelial cells. The TM is Blondin et al. have reported that human TM cells secrete CCL2/MCP-1 in
composed of three main consecutive regions which define the filtering a constitutive manner, whereas the secretion of IL-8 occurs only after the
portion of the TM: the uveal meshwork, the corneoscleral meshwork and cells were exposed to stimuli such as TNF-α (Blondin et al., 2003).
the juxtacanalicular region (JCT). The aqueous humour flows through CCL2/MCP-1 was shown to increase the AH outflow facility when
the intercellular spaces of the TM and crosses the SC inner wall. It first perfused in enucleated porcine eyes and this may be mediated by
encounters the uveal and corneoscleral TM, which function as self- reduced resistance of SC endothelial cells via altered cell-cell contact
cleaning biological filters before reaching the resistance generating re (Tsuboi et al., 2012). TM cells also secrete VEGF in response to me
gion of the JCT directly underneath the inner wall of Schlemm’s canal. chanical stress and this was suggested as a paracrine pathway for con
JCT-TM cells and SC cells are the main regulators of the outflow resis ventional outflow facility regulation (Reina-Torres et al., 2017; Fujimoto
tance (Abu-Hassan et al., 2014; Stamer and Clark, 2017). et al., 2016).
TM cells have various functions including synthesis and degradation In summary, there is some evidence for local para-inflammation
of collagen, proteoglycans and other ECM components, and phagocy involved in the regulation of AH outflow, mediated by the constitutive
tosis of extracellular debris (Vranka et al., 2015; Stamer and Clark, expression of inflammatory cytokines and infiltration of immune cells.
2017). TM cells express prominent cytoskeletal, complex cell-cell and
cell-matrix attachment and water channels to facilitate rapid changes in 4.3. Increased inflammation in the glaucomatous trabecular meshwork
cell volume following stretch and thus to regulate the aqueous outflow
(Stamer and Clark, 2017). Thus, the outflow occurs both between the Various histologic studies using specimens from glaucoma patients at
cells and through the trabecular cells, and a source of inflammation is the time of trabeculectomy compared with samples from normal (post-
precisely the alteration of the barrier function of the trabecular mesh mortem) non-glaucomatous subjects showed an upregulation of
work. TM cells normally sense increased mechanical stretching forces inflammation-associated genes in the TM, which may be involved in the
due to IOP elevation and respond by upregulating the secretion of MMPs initiation or progression of glaucoma. Using immunochemistry and
and TIMPs (Bradley et al., 1998; De Groef et al., 2013). It seems that confocal microscopy, Baudouin & his colleagues clearly showed den
MMPs contribute to conventional aqueous outflow homeostasis in their dritiform inflammatory cells infiltrating the TM, associated with a dra
capacity to remodel extracellular matrices (Acott et al., 2020). matic decrease of TM cells in glaucoma patients (Baudouin et al., 1999,
Baudouin et al., 2012; Hamard et al., 2002) (Fig. 2). Liton et al. showed
4.2. Inflammatory cytokines and aqueous outflow homeostasis statistically significant upregulation of several genes associated with
inflammation and the acute-phase response, including ELAM-1, CXCL-6,
There is some evidence that local para-inflammation plays a regu CCL5, immune-associated nucleotide and IL-1 receptor type II in
latory role in outflow facility through the TM. TM cells secrete various cultured TM samples of POAG patients compared to human
growth factors and cytokines in response to mechanical stretching non-glaucomatous TM samples (Liton et al., 2006). More recently,
(Shifera et al., 2010; Saccà et al., 2015), including IL-1, IL-6, IL-8, and Taurone et al. (2015), confirmed the infiltration and activation of in
TNF-α (Alvarado et al., 2005a; Liton et al., 2005a). Some of these in flammatory cells, including macrophages, T cells and plasma cells, in
flammatory cytokines have been shown to promote AH outflow facility TM sections of glaucomatous compared to normal specimens. They
in human and animal models, suggesting an autocrine feedback loop found significantly increased expression levels of IL-6, IL-1β and TNF-α
aimed at restoring normal IOP values in response to the mechanical in TM specimens of POAG patients with high IOP. They suggested that
stress produced by IOP elevations (Alvarado et al., 2015). Birke et al. macrophages produce pro-inflammatory cytokines, which leads to an
(2011), demonstrated increased TM outflow in response to perfusion of acute inflammatory response and recruitment of other immune cells,
IL-1α and Il-1β in human TM. This was partly mediated by the induction including T cells. Micera et al. (2016), showed increased expression of
of the expression of MMPs (MMP-3 and MMP-9), and by the induction of various cytokines (IL-10, IL-6, IL-7, IL-12, mitochondrial intermediate
endothelial leukocyte adhesion molecule (ELAM)-1 (E-selectin), which peptidase (MIP) 1α/δ and soluble TNFR1), Th1/Th2 (IL-2, IL-3, IL-4,
is a well-known mediator in the first step of inflammation before dia IL-5), pro-fibrogenic growth factors (VEGF, TGF-β1) in the glaucoma
pedesis (Bradley et al., 1998). Another inflammatory cytokine IL-6 tous TM, suggesting an intense inflammatory reaction in patients un
partially increased outflow facility in perfused human organ cultures, dergoing trabeculectomy. Fractalkine (CX3CL1) is another
through modulation of endothelial permeability and induction of MMPs, pro-inflammatory chemokine, which induces adhesion and retention
resulting in ECM degradation (Liton et al., 2005a). Furthermore, TNF-α of monocytes and T cells into inflammatory tissue (Jones et al., 2010).
combined with IL-1α or IL-1β was shown to increase outflow facility The expression of CX3CL1 and its receptor (CX3CR1) were found to be
associated with an intense synergistic increase in MMP-3 and MMP-12 increased in TM specimens of patients undergoing trabeculectomy
through a mechanism partially mediated by the induction of IL-1 re (Baudouin, 2012) (Fig. 3). Interestingly, a lower inflammatory cell
ceptors (Kelley et al., 2007). density and a significantly lower level of CX3CL1 expression were
It has also been suggested that cytokines produced by TM cells could observed when patients were treated with an anti-inflammatory agent
act rapidly to increase the endothelium permeability, especially at the (topical 0.1% indomethacin, or fluorometholone) prior to surgery
level of the juxtacanalicular tissue, and by inducing the expressions of (Baudouin, 2012).
TM MMPs leading to ECM degradation and remodeling. Alvarado et al.
demonstrated that some cytokines, including IL-1α, IL-1β, IL-8 and TNF- 4.4. Aqueous humour cytokines in glaucoma
α increased the permeability of cultured SC endothelial cells exposed to
laser irradiation (Alvarado et al., 2005a, 2005b). They also demon The immune privilege of the aqueous humour is maintained by im
strated that intracameral infusion of autologous macrophages in rabbits mune regulatory and/or suppressive soluble and membrane-bound
increased outflow facility 2-fold in a rapid and sustained manner, sug molecules, along with an efficient blood-aqueous barrier, which pre
gesting that the innate immune system, especially mono vents inflammation. The abnormal immune-inflammatory response
cytes/macrophages, could play a role in aqueous outflow homeostasis mediated by infiltration of immune cells in POAG is supported by the
(Alvarado et al., 2010). It was subsequently confirmed that cultured altered cytokines profile in the anterior chamber (Pinazo-Durán et al.,
human TM cells from non-glaucomatous subjects were able to secrete 2013). The source of these cytokines in the anterior chamber of glau
various chemotactic cytokines (IL-8, chemokine C-X-C ligand (CXCL)-6 coma patients is not clear, and may be the result of secretion from
10
Fig. 2. Inflammatory damage of the glaucomatous trabec

ular meshwork. A: En-face image of a normal trabecular
meshwork with many trabecular cells, stained red by pro
pidium iodide, few vimentin-positive cells (bright green),
and autofluorescent extracellular matrix fibers (mild green).
Confocal microscopy in a donor bank eye after dissection of
the trabecular meshwork.
B: Glaucomatous trabeculum in a surgically taken specimen:
very few remaining cells (red) and high level of extracellular
matrix.
C: higher magnification. The trabeculum is mainly
composed of paucicellular extracellular matrix (from Bau
douin C et al. In vitro and in vivo experimental studies on
trabecular meshwork degeneration induced by benzalkonium
chloride (an American Ophthalmological Society thesis). Trans
Am Ophthalmol Soc. 2012;110:40-63, with permission from
The American Ophthalmological Society).
D: Inflammatory dendritiform cells (green vimentin stain
ing) in the cribriform layer of a trabecular meshwork sur
gically removed at time of trabeculectomy (same reference).
E: Cryosection of trabeculectomy specimen infiltrated by
many inflammatory dendritiform cells (vimentin staining).
(For interpretation of the references to colour in this figure
legend, the reader is referred to the Web version of this
article.)
various ocular resident cells in the TM, iris and ciliary body, and/or from patients with mild visual field defects, supporting a correlation between
diffusion from the vitreous humour or the corneal surface (Wong et al., elevation of IL-8 and the severity of POAG (Kuchtey et al., 2010). Takai
2015; Noma et al., 2010). Alternatively, the AH proteome of glaucoma et al. reported increased IL-8 levels in the AH of patients with POAG or
patients indicates the presence of significantly higher levels of some exfoliation glaucoma, together with increased level of TGF-β1 compared
proteins known to play a role in mediating oxidative stress, apoptosis, with aqueous levels in non-glaucoma patients (Takai et al., 2012). IL-8
inflammation and/or immunity. Most of these are plasma proteins, was overexpressed in conjunction with serum amyloid A (SAA), which
suggesting that some glaucoma disease stages may be associated with a is expressed in high levels in glaucomatous TM cells compared to
breakdown in the blood-aqueous barrier (Anshu et al., 2011). Further non-glaucomatous TM cells, and is known to play a role in inflammation
more, it has been suggested that proteins expressed in the anterior and tissue repair (Wang et al., 2008; Takai et al., 2012). Increased levels
chamber, in addition to reflecting TM dysfunction, could diffuse to the of aqueous TNF-α in POAG patients have also been reported in some
posterior segment, triggering activation of glial cells and participating in studies (Cvenkel et al., 2010; Sawada et al., 2010; Balaiya et al., 2011),
RGC apoptosis (Saccà et al., 2016). but not in others (Kuchtey et al., 2010; Takai et al., 2012).
Most studies have compared AH cytokines expression between In contrast, decreased levels of IL-2 and IL-6 were shown in the
glaucoma and non-glaucoma patients undergoing trabeculectomy or anterior chamber of glaucoma patients (Hautala et al., 2012; Takai et al.,
routine cataract surgery, respectively. As shown by Freedman et al. 2012; Borkenstein et al., 2013). IL-6 is known to induce a Th2-type of
patients with open-angle glaucoma (OAG) have higher aqueous levels of immune-inflammation (Diehl & Rincon, 2002) and it was suggested that
cytokines (IL-6, IL-8) and chemokines (CCL2/MCP-1, CXCL1) associated this plays a role in maintaining normal outflow facility in TM (Liton
with elevated IOP, confirming that mechanical stress produced by IOP et al., 2005a), which may have neuroprotective properties in glaucoma
may be responsible for cytokine production (Freedman et al., 2013). (Sappington et al., 2006). Chua et al. (2012) found increased levels of
Increased aqueous IL-8 levels were consistently reported in several IL-12, INF-γ and CXCL9 (IL-9) in the AH of POAG patients. Increased
studies in glaucoma patients (Kuchtey et al., 2010; Takai et al., 2012; aqueous levels of IL-12 and INF-γ suggest the activation of a Th1-type
Engel et al., 2014). Kuchtey et al. found that patients with severe visual immune response involving T-cells (Chua et al., 2012) and increased
field defects had higher aqueous concentrations of IL-8 compared to expression of CCL2/MCP-1 suggests the activation of
11
Fig. 3. Assessment of fractalkine (CXCL3)

in trabecular meshwork cells submitted
to benzalkonium or TNF-α. Indirect im
munostaining for fractalkine (in red) in
trabecular cells in vitro (nuclei are counter
stained in blue by DAPI). A: Low, almost
negative fluorescence intensity in basal
condition; B: strong expression following
TNF-α; C: BAK 5 × 10-5% stimulation for 24
h; D: 5 × 10-4% stimulation for 24 h. After
BAK stimulations, cells lost their elongated
form and cell density was reduced. Bars =
50 μm (from Baudouin C et al. In vitro and in
vivo experimental studies on trabecular mesh
work degeneration induced by benzalkonium
chloride (an American Ophthalmological Soci
ety thesis). Trans Am Ophthalmol Soc.
2012;110:40-63, with permission from The
American Ophthalmological Society). (For
interpretation of the references to colour in
this figure legend, the reader is referred to
the Web version of this article.)
monocytes/macrophages. oxidative stress arises from the impaired balance between ROS and
anti-oxidant mechanisms and can promote cell death via mitochondrial
damage, apoptosis, and loss of tissue integrity (Saccà et al., 2015). The
4.5. Mechanisms of chronic inflammation in the glaucomatous TM chronic oxidative stress in the TM may originate from ROS generated by
many cellular sources, but also from light radiation (Osborne et al.,
In glaucomatous TM specimens, the increased extracellular material 2017), endogenous mitochondrial respiration and possibly from me
and thickness of elastic fiber sheaths are associated with oxidative stress, chanical stress (Gonzalez et al., 2000). Glaucoma-affected patients also
premature senescence, altered autophagy and apoptosis which leads to have a significant depletion in the total anti-oxidant potential in the
cell death and excessive loss of TM (Alvarado et al., 1984; Hamard et al., aqueous humour compared to non-affected subjects (Ferreira et al.,
2002; Baudouin et al., 2012; Tektas et al., 2009) (Fig. 3). As described 2004).
above, local para-inflammation seems to be involved in the regulation of ROS have a role in the pathogenesis of glaucoma by stimulating the
AH homeostasis, through the constitutive expression of inflammatory apoptotic and inflammatory pathways at the level of the TM. It was
cytokines and infiltration of immune cells. A disruption of the suggested that oxidative stress might induce premature senescence of
cytokine-mediated feedback loop in response to mechanical stress has TM cells. In vitro, TM cells exposed to chronic oxidative stress showed a
been proposed as a mechanism for the progression to elevated IOP marked decline in proteasome activity, associated with premature
(Alvarado et al., 2015). Other stress stimuli, including oxidative, toxic or senescence and decreased cell viability (Caballero et al., 2003). Elevated
vascular stress may shift the physiological immune balance over a cellular oxidative stress was shown to activate senescence markers such
chronic-cumulative period leading to a chronic inflammatory degener as cyclin-dependent kinase inhibitors p16 and p21 (Fatma et al., 2009).
ative process. This was associated with several mechanisms, including vascular
dysfunction, mitochondrial dysfunction, declined autophagy, altered
4.5.1. Chronic oxidative stress, mitochondria, senescence and inflammation gene expression, oxidative stress and apoptosis (Caballero et al., 2003;
Oxidative stress and vascular damages are considered as two major Izzotti et al., 2006; Liton et al., 2005b, 2009; Baleriola et al., 2008).
alterations in the TM related to glaucoma (Zhao et al., 2016). During a Senescent cells are metabolically, highly active and secrete an array of
chronic disease such as glaucoma, the affected tissues and TM first suffer proinflammatory cytokines and chemokines, growth factors and extra
from a chronic low-grade oxidative insult, which lasts for decades and cellular degrading protein (Coppé et al., 2008; Sreekumar et al., 2020).
increases in level with age (Saccà et al., 2016). Even small concentra Mitochondria are not only the main endogenous source of ROS, but
tions of ROS can produce changes in cellular redox state and affect they are also one target of the oxidative stress leading to mtDNA damage
enzyme activity, protein-protein and DNA-protein interactions and (Izzotti et al., 2010; Saccà et al., 2015). Thus, oxidative stress can cause
transcription factors (Finkel, 1998; Finkel and Holbrook, 2000). Chronic
12
mitochondrial failure and increase endogenous production of oxidative 4.5.3. Glaucoma medications toxicity
stress from the mitochondria, thus establishing a vicious cycle (Saccà Most of the human studies looked at specimens taken at time of
et al., 2016). Mitochondrial oxidative stress is associated with a signif surgery, mostly in late stages of glaucoma. However, they have rarely
icant decrease in mitochondrial potential membrane, and a rapid acti investigated the relationship between increased aqueous levels of cy
vation of transcription factors involved in caspase-mediated apoptosis tokines and preoperative treatments, as patients undergoing glaucoma
and excessive autophagy leading to cell death (Saccà et al., 2015; surgery are likely to have received more treatments over a longer
Osborne et al., 2017). duration. In one study, aqueous levels of IL-8, TGF-β1, and SAA were
On the other hand, the Nrf2 signaling pathway, which is known to positively associated with the number of topical glaucoma medications
protect from the effect of oxidative stress, was shown to be down- (Takai et al., 2012). Therefore, it is possible that the increased exposure
regulated in human glaucomatous TM cells compared with normal TM to toxic preservatives (i.e. benzalkonium chloride [BAK]) could induce
cells (Cheng et al., 2017). Oxidative stress not only causes direct TM cell local inflammation. This could result in a vicious cycle, i.e. the more
damage and participates in TM matrix accumulation, but also activates treatments administered, the greater the quantity of toxic compounds
the redox-responsive factors NF-κB and mitogen-activated protein ki and inflammatory cytokines diffusing from the surface to deeper struc
nases (MAPKs), resulting in the transcription of inflammatory cytokines. tures, which leads to TM inflammation and a higher resistance to AH
When exposed to chronic oxidative stress, TM cells in primary culture outflow, a subsequent increase in IOP, and the requirement for more
have been shown to produce inflammatory markers, including IL-1α, treatments (Baudouin et al., 2010, Baudouin et al., 2012). Indeed,
IL-6, IL-8 and ELAM-1, through sustained activation of the NF-κB penetration of BAK deeper into the eye, including the TM and the lens,
pathway (Li et al., 2007; Liton et al., 2005a). These inflammatory stress was shown in rabbit eyes exposed to standard concentrations of BAK
markers have been associated with high-tension glaucoma of different (Brignole-Baudouin et al., 2012; Desbenoit et al., 2013). In patients with
aetiologies (Wang et al., 2001). The IL-1/NFκB pathway has been sug OHT or POAG, increased flare levels were also shown in the anterior
gested as protective in the short term, but amplification of this pathway chamber of eyes receiving BAK-preserved anti-glaucomatous eye drops
due to prolonged stress may lead to pathologic tissue changes. In sum compared to preservative-free eye drops, suggesting that BAK exerts its
mary, the inflammatory reaction in the glaucomatous TM is likely to be effect on the blood-aqueous barrier in the anterior chamber (Stevens
initiated by oxidative stress, leading to activation of NF-κB signaling and et al., 2012; Kestelyn et al., 2019). In a rat model, subconjunctival in
the release of pro-inflammatory mediators, including TNF-α, which in jections of BAK 0.01% were shown to cause TM cell death and induce
turn are able to modify the ECM (Saccà et al., 2016b). toxic trabecular damage resulting in a significant reduction of the AH
outflow facility and a sustained rise in IOP (Baudouin, 2012). In human
4.5.2. TGF-β2 TM in culture, BAK induced cell death, DNA fragmentation, and gene
TGF-β2 is believed to play a major role in TM degeneration. Elevated expression alterations (Izzotti et al., 2015).
levels of TGF-β2 have been found in the AH of POAG patients compared BAK also increased the generation of inflammatory mediators
to normal patients (Tripathi et al., 1994a; Inatani et al., 2001; Ozcan (Fractalkine, also called CX3CL1) and decreased TM cell expression of
et al., 2004; Min et al., 2006; Trivedi et al., 2011, Agarwal et al., 2015). stromal cell-derived factor-1 (SDF-1, CXCL12), a protective chemokine
This factor is known to promote fibrosis through increased ECM syn with anti-apoptotic properties (Khan et al., 2008). Consequently,
thesis and deposition (Fuchshofer and Tamm, 2009; Zhavoronkov et al., long-term administration of preserved anti-glaucoma treatments con
2016). TGF-β2 has been shown to reduce outflow facility when perfused taining BAK may play a role in TM cell loss through oxidative stress,
into cultured human anterior segments and to increase IOP in human chronic inflammatory changes, and apoptosis within the glaucomatous
organ culture models (Gottanka et al., 2004; Fleenor et al., 2006). TM (Baudouin et al., 2012; Hamard et al., 2003; Izzotti et al., 2015). This
TGF-β2 is thought to contribute to the development of glaucoma by vicious cycle might clinically appear as an apparent progressive loss of
increasing the secretion of ECM materials, facilitating ECM crosslinking, efficacy of topical IOP-lowering drugs, namely the more drugs, the
increasing size and rigidity of TM cells, reducing protease activity and greater the toxic reaction, leading to a higher IOP despite initial effi
the formation of cellular stress fibres in the TM (Fleenor et al., 2006; ciency of drugs (Baudouin, 2012). Therefore, a progressive cyclic evo
Wordinger et al., 2007; Tovar-Vidales et al., 2013). In addition, TGF-β2 lution may occur over the long term in glaucomatous patients,
was found to induce senescence-associated changes in human TM cells characterised by progressive inflammation caused by inflammatory in
(Yu et al., 2010) and to induce synthesis and secretion of ET-1, a potent filtrates and cytokine release, which is either pre-existing and/or
vasoconstrictor that elicits TM cell contraction through endothelin-A aggravated by topical treatments or purely iatrogenic. The subsequent
receptor signaling (Von Zee et al., 2012). TGF-β2 has been shown to diffusion of these infiltrates into the deep structures within the eye
increase lipid peroxidation and ROS production in TM cells (Yu et al., participate in an increased resistance to aqueous humour outflow, which
2010), reinforcing the cascade of events occurring in POAG, in an order requires additional drugs to control IOP and eventually surgery, whose
that remains to be determined, TM cell senescence, TGF-β dysregulation prognosis will be negatively influenced by inflammatory changes within
and overexpression, TM oxidative stress, TM cell loss, matrix accumu the anterior segment. Such hypothetical model is proposed in Fig. 4.
lation and further reduction in AH outflow (Baudouin, 2012).
The mechanisms responsible for regulating endogenous synthesis 5. Ocular surface inflammation in glaucoma
and secretion of TGF-β2 within anterior chamber are not well known.
Nevertheless, it has been shown that human TM cells can secrete TGF-β2 Inflammation, free radical production, and apoptosis are closely
(Tripathi et al., 1994b), that TGF-β2 activation is enhanced by senes related processes in ocular cells. The most prominent and visible con
cence (Chhunchha et al., 2017), and that senescent cells may release sequences of inflammation in glaucoma are those occurring at the ocular
more pro-inflammatory mediators (Sreekumar et al., 2020), and surface level. Ocular surface disease (OSD) is therefore very common in
possibly more TGF-β2. these patients (Erb et al., 2008; Ghosh et al., 2012; Baudouin et al.,
Thus, a localised constitutive expression and release of TGF-β2 by TM 2013). In an observational cross-sectional study, 51% of patients with
cells may promote or exacerbate elevation of IOP in POAG (Pervan et al., glaucoma or OHT had significant OSD, which was mild to moderate in
2016). 30% of patients and severe in 21% (Baudouin et al., 2013). Glaucoma
However, this growth factor also has a dual effect since it is known to patients commonly complain of ocular symptoms, including foreign
have immunosuppressive properties and is responsible for anterior body sensation, eye redness, pruritus, pain, photosensitivity and blurred
chamber-associated immune deviation, a mechanism that protects the vision. Adverse changes in tear film stability, tear osmolarity, conjunc
eye from inflammation and immune-related tissue damage (Wilbanks tival hyperaemia, and conjunctival or corneal damage are frequently
et al., 1992; Streilein, 1999). observed (Baudouin et al., 2013; Wong et al., 2018) (Fig. 5). Ocular
13
5.1. Subclinical inflammation at the ocular surface
Patients on long-term glaucoma treatment often show significant

subclinical ocular surface inflammation suggestive of overexpression of
HLA-DR, ICAM-1, cytokines, chemokines, infiltration of immuno-
inflammatory cells (monocytes and T-cells) in the conjunctiva and
cornea, and fibroblast activation in the conjunctiva and subconjunctival
space (Baudouin et al., 1999) (Fig. 6). Increased secretion of cytokines
(IL-6 IL-8, and IL-10) have been reported in conjunctival epithelial cells
of glaucoma patients treated with preserved latanoprost or timolol eye
drops compared to normal eyes (Pisella et al., 2004; Baudouin et al.,
2004, 2008). In addition, increased levels of cytokines (IL-1β, IL-2, IL-5,
IL-6, IL-8, IL-10, IL-13, IL-15, IL-17, MCP-1/CCL2, TNF-α) have been
reported in tears of POAG patients on medical therapy (Malvitte et al.,
2007; Benitez-Del-Castillo et al., 2019). Levels of both Th1 (IFN-γ, IL-2)
and Th2 (IL-4, IL-5, IL-10) cytokines have also been found at signifi
cantly higher levels in the tears of patients on topical glaucoma therapy
(Malvitte et al., 2007). Interestingly, Th1 cytokines have shown the most
marked increase, suggesting a chronic pro-inflammatory reaction
resembling dry eye disease (Baudouin et al., 2008), whereas Th2 cyto
kines are associated more with allergic reactions, demonstrating a
possible combination of the two mechanisms. This is consistent with the
Fig. 4. Schematic proposal of possible evolution of glaucomatous patients overexpression of both CCR5 and CCR4 found in the conjunctival
treated over the long term and experiencing potential aggravation of the epithelium of glaucoma patients, two markers of the Th1 and Th2
disease through immunoinflammatory and/or toxic mechanisms. activation pathways, respectively (Baudouin et al., 2008).
surface changes also include effects which are not clinically visible but 5.2. Glaucoma medications and ocular surface inflammation
highly relevant to ocular surface physiology, including decreased goblet
cell density, infiltration by inflammatory cells, a significant decrease in Factors affecting the stability and osmolarity of the tear film induce
the number and density of the central corneal subbasal nerve fibers, and ocular surface damage and initiate inflammatory cascades that generate
a reduction in corneal sensitivity (Broadway et al., 1994a, 1994b; innate and adaptive immune responses, mediated by infiltration of
Martone et al., 2009; Baudouin et al., 2010; Saini et al., 2017; Tiede monocytes and lymphocytes. In this context, it was reported that un
mann et al., 2019). Changes in the meibomian gland morphology and treated OAG patients had decreased basal tear turnover, which may
function have also been frequently reported. Indeed meibomian gland have been caused by glaucoma itself (Kuppens et al., 1995). However, it
dysfunction is strongly associated with treatments over the long-term, has also been consistently shown that the number of antiglaucoma drugs
causing both eyelid inflammation, toxic or immune-allergic blepharitis and the duration of treatment correlates with the severity of glaucoma
and dry eye through tear film instability (Messmer et al., 2005; Arita and are key predictors of significant OSD (Ghosh et al., 2012; Baudouin
et al., 2012; Mocan et al., 2016; Lee et al., 2018). et al., 2013). The cumulative exposure of the most commonly used
preservative (BAK), appears to be one of the major factors leading to
ocular surface inflammation and damage (Ghosh et al., 2012; Iester
et al., 2014; Mastropasqua et al., 2016). BAK induces time- and
concentration-dependent cytotoxic effects on the cells of the ocular
Fig. 5. OSD in glaucomatous patients. A: Allergic reaction to

topical drug: eczematous eyelid.
B: Weakly symptomatic toxic keratopathy marked by extended
fluorescein staining.
C: Post-surgical difference between left eye, free of eyedrops
after trabeculectomy and right eye severely affected by topical
treatments.
D: Toxic pseudopemphigoid with eyelid retraction and
symblepharon.
14
Fig. 6. Inflammatory cells in ocular surface tissues in glaucoma. A: Dendritic cells infiltrating the cornea in a glaucomatous patient (in vivo confocal microscopy,
400μmx400μm).
B: Immunofluorescence staining of dendritiform cells in impression cytology in a multitreated patient: vimentin staining (green), nuclei stained with propidium
iodide (red), confocal microscopy.
C: Conjunctival biopsy taken at the time of trabeculectomy in a multitreated patient: infiltration of the substantia propria by numerous inflammatory cells expressing
vimentin (green). Nuclei are stained in red with propidium iodide. (For interpretation of the references to colour in this figure legend, the reader is referred to the
Web version of this article.)
surface, likely mediated by chronic oxidative stress, which causes already damaged or pathological ocular surface.
inflammation and induction of signals leading to apoptosis and cell
death (Baudouin et al., 2010).
However, the contribution of the active ingredients in the medica 5.3. Corneal barrier dysfunction in glaucoma
tion or the interaction with pathological ocular surface tissues at the
initiation of therapy cannot be ruled out (Pflugfelder and Baudouin, The corneal cell layers are critical in maintaining a healthy and clear
2011; Villani et al., 2016; Mastropasqua et al., 2016). As an example of cornea. In medically controlled glaucoma patients, the cornea is one of
the direct effects of an active compound, topical application of the most altered tissues, with modifications involving all epithelial
preservative-free latanoprost was shown to decrease tear production, layers, subbasal nerve plexus, stroma and endothelium. Glaucoma is also
induce conjunctival goblet cells loss, disrupt corneal epithelial barrier, associated with deleterious effects on corneal endothelium due to
and promote cell apoptosis and inflammation of the ocular surface (Yang topical treatments, elevated IOP and glaucoma surgical procedures
et al., 2018a). Beta-blockers, with or without preservatives, have also (Janson et al., 2018).
been shown to induce ocular surface damage, including corneal staining, Ocular inflammation is also associated with OSD and has been shown
conjunctival goblet cell loss and squamous metaplasia (Aydin Kurna to affect corneal structure and function (Stern and Pflugfelder, 2004). In
et al., 2014). In mice, topical application of preservative-free latanoprost patients with glaucoma, the dendritic cell density has been found to be
has also been shown to increase CD4+ T cells infiltration in the con two to three times higher at the limbus, and more than ten times higher
junctiva. This was associated with increased production of IFN-γ, IL-17 in the central cornea compared to healthy controls (Mastropasqua et al.,
A, TNF-α, IL-1β, activation of MMPs in the conjunctiva, and decreased 2016) (Fig. 6A and B). Inflammatory cytokines (e.g. TNF-α, IL-1β and
production of IL-13, which may be a result of the activation of IFN-γ) and toxic compounds like BAK, have been shown to induce
P38–NF-κB signaling (Yang et al., 2018a). corneal epithelial barrier dysfunction through downregulation of
In summary, OSD in glaucoma is likely to be the result of interactions corneal epithelial cell adhesion molecules and tight-junction proteins
between the ocular surface and the active compounds acting alone or in such as zonula occludens 1 (ZO-1) or occludin (Pauly et al., 2009;
combination with the preservatives and excipients. In this context, OSD Kimura et al., 2013).
may manifest from a progressive toxic and/or immune-inflammatory In general, the ocular surface is extensively supplied by sensory and
reaction or be aggravated when eye drops are administered on an autonomic nerve fibers that play a crucial role in maintaining ocular
surface homeostasis (Belmonte et al., 2017). Chronic ocular
15
inflammation can therefore lead to decreased corneal sensitivity and a abnormal expressions of TGF-β and MMPs, which may promote scarring
consequent neurosecretory block that reduces reflex tear secretion of the filtering blebs following glaucoma-filtering surgery (Leng et al.,
(Lambiase et al., 2011). Neurogenic inflammation is produced princi 2011). In this context, specific pro-inflammatory cytokines, including
pally through release of neuromodulators, such as substance P and TNF-α and IL-6, have been suggested as responsible for bleb scarring and
calcitonin-gene related peptide (CGRP), leading to edema and break failed trabeculectomy when diffusing in the subconjunctival spaces
down of the blood-tissue barrier (Beuerman and Stern, 2005). (Cvenkel et al., 2010). Chong et al. (2010) found increased levels of
Corneal barrier dysfunction may cause cytokine penetration, thereby MCP-1 in the tears of patients treated with topical anti-glaucomatous
contributing to inflammation and damage of the corneal endothelium as drugs, which was associated with early postoperative scarring in need
well as possibly causing damage to deeper structures in the anterior of postoperative bleb needling. Recently, Hayek et al. (2019) used
segment. The influence of toxic compounds and/or inflammatory cyto angio-optical coherence tomography (OCT) and demonstrated that a
kines that diffuse from the ocular surface to deeper structures, such as higher conjunctival vascular density is associated with poorer prognosis
TM, is still speculative, but studies have suggested that this may after surgery, including a higher postoperative IOP and a greater need
contribute to degenerative anterior processes associated with POAG for needling. Furthermore, it has been suggested that goblet cells may
(Baudouin, 2012). act as aqueous humour pathways after surgery (Amar et al., 2008), and
that preoperative goblet cell reduction induced by BAK may have
deleterious effects (Baudouin et al., 2019; Rolando et al., 1991). In line
5.4. Subconjunctival inflammation and fibrosis in glaucoma with this, Agnifili et al. (2016) reported negative outcomes in cases with
reduced goblet cell density, due to chronic inflammation and/or toxic
The development of subconjunctival fibrosis has been reported in drugs. Similarly, Souchier et al. (2006) found a higher mucin 5AC
patients treated with antiglaucomatous drugs over a long duration, is (MUC5AC) expression and lower subclinical inflammation (HLA-DR) in
potentially due to an increase in fibroblast density in the subepithelial successful glaucoma surgery compared with failed surgery.
substantia propria, related to an increase in inflammatory cells (Sher
wood et al., 1989; Baudouin et al., 1999; Broadway et al., 1994a,
1994b). It has also been shown that POAG patients undergoing a deep 5.5. From subclinical to severe ocular surface changes in glaucoma
sclerectomy, and with a long history of anti-glaucomatous eye drops
have increased expression of MMPs, especially MMP-9 and TIMPs, It has become clear that inflammatory responses induced by glau
which could impair the healing process (Helin-Toiviainen et al., 2015). coma drugs lead to further ocular surface damage and the development
More evidence has been found that sub-clinical, abnormal pre- of a self-perpetuating vicious cycle of inflammation (Stevenson et al.,
operative inflammation due to a cumulative exposure to BAK- 2012; Baudouin et al., 2012, 2018). A model of frequency of ocular
preserved eye drops are likely to be responsible for an exaggerated surface changes from subclinical to extremely severe alterations is pro
wound healing process that blocks aqueous outflow in the subcon posed in Fig. 7. Most likely, such changes will gradually worsen as a
junctival space. This results in external bleb scarring and failure of result of aging and the need for additional IOP-lowering eye drops, with
filtration surgery (Broadway et al., 1993; Sherwood et al., 1989; Bau the increasing damage to the ocular surface making it more sensitive and
douin, 2012; Helin et al., 2011) (Fig. 6C). vulnerable to further treatments. One difficulty in assessing subclinical
Prolonged use of some topical anti-glaucomatous eye drops may be changes and subtle clinical abnormalities is that is remains impossible to
associated with enhanced Tenon’s capsule fibroblasts proliferation and determine whether such subclinical inflammation will progressively
Fig. 7. Proposal for a schematic representation of increasing severity levels and estimated frequency of various levels of ocular surface disease in
glaucoma patients. Cumulative frequencies are given by including the lower level of severity, namely asymptomatic (with only histological lesions), mildly
symptomatic and more severe cases.
16
increase and become clinically relevant or remain stable. significantly inhibited the expression of the monocyte chemoattractant
CCL2/MCP-1 and the leukocyte adhesion molecule ICAM-1 while at the
6. Modulation of inflammation in glaucoma: perspectives and same time reducing the infiltration of MHC class-II positive inflamma
future directions tory leukocytes (Abcouwer et al., 2013).
Innate and adaptive inflammatory mechanisms mediated by resident 6.1.1.2. Azithromycin. Azithromycin is a widely used semi-synthetic
cells are necessary to maintain healthy eye structures. However, the macrolide antibiotic with anti-inflammatory and immunomodulatory
para-inflammation can quickly go from being positive to becoming toxic properties independent of its antibacterial effects (Zarogoulidis et al.,
and become a contributing factor to the degeneration of ocular tissues. 2012). Varano et al. recently reported the evidence of the neuro
There is evidence that stress stimuli, including increased IOP or protective effect of azithromycin in an experimental model of acute
decreased ocular blood flow, associated with chronic oxidative stress glaucoma induced by transient elevation of IOP (Varano et al., 2017). A
can tip the balance from beneficial para-inflammation to toxic levels single dose of azithromycin given systemically at the end of ischemia
participating in TM and retinal/ONH degeneration in glaucoma (Xu produced a down-regulation of gene products related to necrotic and
et al., 2009; Jiang et al., 2020). In addition to its potential involvement apoptotic cell death, including reduced calpain activity and prevention
in TM and retinal/ONH degeneration, inflammation also plays a major of Bcl-2-associated death promoter (Bad) upregulation. The observed
role in initiating and perpetuating OSD in glaucomatous patients, which neuroprotection was also associated with a significant inhibition of
may decrease the effectiveness of IOP-lowering treatments and increase MMP-2/MMP-9 activity and extracellular signal-regulated kinases
the risk of surgical failure (Baudouin et al., 2010, Baudouin et al., 2012). (ERK) 1/2 phosphorylation. Azithromycin may therefore provide neu
Various therapeutic approaches have been proposed to prevent or roprotection by modifying the inflammatory state of the retina following
modulate the excessive inflammatory reactions in glaucomatous eyes. ischemia/reperfusion injury that, in turn, affects neuronal survival in
Some well-known products appear to have beneficial effects on neuro central areas (Varano et al., 2017; Adornetto et al., 2019).
inflammation in animal glaucoma models, but have not yet been tested
in clinical studies. 6.1.1.3. Adenosine receptor antagonists. Caffeine, by blocking A2A re
ceptors is known to prevent synaptotoxicity, excitotoxicity and neuronal
loss. In addition, it has been shown to have anti-inflammatory properties
6.1. Tentative targets for treating neuroinflammation in the CNS, namely by attenuating microglia-mediated neuro
inflammation (Brothers et al., 2010). In this context, caffeine and
Therapies aimed at modulating the immune and inflammatory re adenosine receptor antagonists have been suggested as possible thera
sponses are attractive approaches for limiting ONH damage and the loss peutic options to manage RGC loss in glaucoma (Madeira et al., 2016a,
of RGCs associated with glaucoma (Adornetto et al., 2019; Karlstetter 2016b). In rats with OHT induced by laser photocoagulation of the
et al., 2015). Studies using animal models have shown that a number of trabecular meshwork and limbal veins, caffeine (1 g/L) administered ad
drugs have the ability to modulate the reactivity of glial cells and their libitum in the drinking water was shown to inhibit the overall inflam
inflammatory response. However, even though neuroprotection has matory response as well as prevent the retinal microglia-mediated
been shown in rodent models, many drugs that have demonstrated po neuroinflammatory response. The elevated retinal expression of TNF-α
tential in experimental models have failed or are missing in a clinical and IL-1β induced by the ocular hypertension also decreased. In addi
setting and further investigations are needed in primates and humans. tion, caffeine was able to prevent OHT-induced microglia reactivity,
including in the contralateral eye. Overall, the study suggested that
6.1.1. Suppression of glial cell activity caffeine preserves RGC survival (Madeira et al., 2016b). Similar effects
were recently obtained with caffeic acid phenethyl ester (CAPE) in a rat
6.1.1.1. Minocyclines. Minocycline is a second-generation tetracycline glaucoma model with optic nerve crush injury (Jia et al., 2019). RGC
with well-known anti-inflammatory activity (Abcouwer et al., 2013). loss was significantly reduced in CAPE-treated animals compared with
The neuroprotection provided by minocycline appears to be mediated the non-treated group. This was associated with decreased expression of
by two mechanisms: attenuation of innate and adaptive immunity, in inflammatory cytokines, including IL-8, IL-6, iNOS, cyclo-oxygenase-2,
particular the prevention of microglia activation, and blockade of the TNF-α and CCL2/MCP-1, and by inhibition of the NF-κB signaling in
apoptotic cascade. Long-term treatment of DBA/2 J mice with minocy caffeine-treated rats. Hypertrophy of astrocytes and Müller cells caused
cline was found to suppress early microglial activation and to signifi by optic nerve crush was also attenuated (Jia et al., 2019).
cantly improve neuronal retrograde tracing from the superior colliculus,
the main retinal synaptic target in rodents (Bosco et al., 2008). In an 6.1.1.4. TNF-α receptor antagonists. Etanercept is a recombinant
experimental model of glaucoma using intracameral injection of chon chimeric protein generated by fusing the ligand-binding portion of
droitin sulfate in rats, minocycline (30 mg/kg per day for 2 weeks, i. p.) human TNFR2 and the Fc portion of human IgG1. It is approved for
significantly reduced microglial (Iba, ED1) and astrocyte (GFAP) various autoimmune diseases, including rheumatoid arthritis, juvenile
markers and myelin alteration, without effect on IOP (Bordone et al., idiopathic arthritis, ankylosing spondylitis, and psoriatic arthritis
2017). Minocycline also preserved the anterograde transport of cholera (Nanda and Bathon, 2004; Ramiro et al., 2011). When administered
toxin B (CTB), a reliable tracer, from the retina to the superior colliculus intraperitoneally in mice with OHT produced by episcleral vein
and LGN. Although these results suggest protection in the early stage of cauterization, etanercept inhibited TNF-α generation in the retina, and
glaucoma, it was also demonstrated that minocycline (22 mg/kg, i. p.) reduced the reactive microglia and astrogliosis around the ONH. Over
improved RGC survival in other experimental glaucoma models with all, etanercept was shown to prevent RGC loss and axon degeneration in
elevated IOP (Levkovitch-Verbin et al., 2006). One of the mechanisms mice with OHT (Roh et al., 2012).
may be the increased gene expression of Bcl-2, as indicated by the ob
servations from a rat glaucoma model with optic nerve transection 6.1.1.5. cAMP phosphodiesterase (PDE) inhibitors. Ibudilast, a PDE type
(Levkovitch-Verbin et al., 2014a, Levkovitch-Verbin et al., 2014b). In 4 (PDE4) inhibitor, has been proposed as a potential treatment of
addition to showing neuroprotective qualities in rat glaucoma models, neurodegenerative diseases (Chen et al., 2020) and is currently under
minocycline treatment was also effective in preventing vascular clinical investigations for the treatment of multiple sclerosis (Fox et al.,
permeability and inflammation following retinal ischemia-reperfusion 2018). In ocular hypertensive rats, Cueva Vargas et al. (2016) demon
(IR) injury in a model of retinal neurodegeneration with breakdown of strated that intravitreal administration of ibudilast dampened macroglia
the blood-retinal barrier (Abcouwer et al., 2013). Here, minocycline
17
and microglia reactivity in the retina and optic nerve compared to 6.2. Treatment of anterior segment inflammation
vehicle injection. Ibudilast also reduced to baseline level proin
flammatory cytokines (including TNF-α, IL-1β, IL-6, migratory macro Based on TM degeneration pathophysiology, there is a need for anti-
phage inhiobitory factor [MIF-1]). It also promoted RGC survival, oxidative and anti-inflammatory strategies to treat inflammation in the
prevented axonal degeneration, and improved anteretrograde axonal anterior segment and restore TM function. Although timolol has been
transport. Thus, the PDE4 signaling may be considered as a potential shown to exert a direct anti-oxidant activity that protects human
target in glaucomatous neuroinflammation. endothelial cells from oxidative stress in vitro (Izzotti et al., 2008), no
studies have provided evidence of this in vivo protective mechanism in
6.1.1.6. Fas receptor antagonists. Krishnan et al. (2019) recently report glaucoma patients. Animal studies of IOP-lowering eye drops, such as
the inhibition of neuroinflammation and prevention of axon degenera latanoprost, showed that although these medications can lower IOP,
tion and RGC death in an inducible mouse model of glaucoma treated they did not reverse or improve the oxidative stress or damage caused by
with an intravitreal injection of a Fas receptor antagonist (ONL1204). glaucoma (Fahmy et al., 2018).
Neuroprotection was correlated with a significant reduction of micro
glial and/or infiltrating macrophages activation, and inflammatory cy 6.2.1. Flavonoids
tokines (including TNF-α, IL-1b, IL-6 and IL-18) and chemokines Flavonoids have several bioactive properties including anti-oxidant,
(MIP-1α, MIP-1β, MIP-10, MCPI, and IP10). anti-inflammatory and neuroprotective effects (Milbury, 2012). It has
also been reported that they may reduce oxidative stress and improve
6.1.2. Suppression of oxidative stress ocular blood flow in POAG (Khoo et al., 2010). Recently, a flavonoid,
In view of the role of oxidative stress-related mechanisms in neuro myricetin was shown to reduce the ROS-induced oxidative stress, to
inflammation, anti-oxidant strategies represent a possible approach as down-regulate senescence markers, and to lower the expression levels of
an immunomodulation strategy in glaucoma. inflammatory cytokines including (IL-1α, IL-1β, IL-6, Il-8, TNF-α, VEGF,
TGF-β1 and TGF-β2) in TM cells from POAG patients (Yang et al.,
6.1.2.1. Coenzyme Q10. Coenzyme Q10 is a mitochondrial-targeted 2018b). When administered in rats with chronic OHT induced by
anti-oxidant with known neuroprotective activity (Davies et al., 2017; intracameral injection of hyaluronic acid for 6 weeks, oral myricetin
Martucci et al., 2019). This product is claimed to protect RGCs (Nucci (25, 50 or 100 mg) effectively prevented IOP elevation. Moreover,
et al., 2007) and it is currently under investigations in clinical trials. In myricetin reduced ROS levels and inflammatory cytokines (IL-6, IL-8) in
an open randomised controlled trial, topical coenzyme Q10 (one drop the aqueous humour and in the TM cells of these hypertensive rats (Yang
twice daily for 12 months) associated with vitamin E administered in et al., 2018b).
OAG patients improved the inner retinal function (pattern electroreti
nogram) with an enhancement of the visual cortical responses (Parisi 6.2.2. Omega-3 fatty acids
et al., 2014). Significant levels of co-enzyme Q10 were detected in the Omega-3 fatty acids, like docosahexaenoic acid (DHA) and eicosa
vitreous humour after a single drop administration (Fato et al., 2010), pentaenoic acid (EPA), have well-documented anti-inflammatory
and there was a significant reduction in the levels of superoxide dis properties (San et al., 2005). These essential fatty acids may have
mutase in the aqueous humour after administration in patients with therapeutic potential in glaucoma or may be beneficial in terms of
pseudo-exfoliative glaucoma (Ozates et al., 2019). A randomised, glaucoma prevention (Saccà et al., 2019). Recently, three months sup
double-blind and controlled study is currently being performed to assess plementation of oral omega-3 supplementation was shown to signifi
the neuroprotective effect of co-enzyme Q and vitamin E on the time to cantly reduce IOP in normotensive adults and in pseudoexfoliative
visual field progression up to 36 months in POAG patients (Quaranta glaucoma (Downie et al., 2018; Villadoniga et al., 2018).
et al., 2019) (Clinicaltrials.gov NCT03611530).
6.3. Treatment of ocular surface inflammation
6.1.2.2. Ginkgo biloba. In a randomised, placebo-controlled study, oral
administration of Ginkgo biloba extracts (40 mg 3 times daily for one Treatment of the ocular surface may be useful in glaucomatous pa
month) improved pre-existing visual field damage in patients with tients with OSD and before filtering surgery. The most appropriate way
normal tension glaucoma (Quaranta et al., 2003, 2014). The mechanism to control and inhibit surface inflammation is to identify the components
of action may due to free radical scavenger effects, but also on the responsible for OSD, whether the active compound or one of the
glutamate signaling and the preservation of the mitochondrial function excipient of a treatment, and remove or replace it by a more tolerated
(Kolko, 2015). Nevertheless, these results have not been confirmed in compound. This may also be achieved by using laser therapy or surgery
other clinical trials (Guo et al., 2014a, Guo et al., 2014b), and therefore to reduce IOP. Indeed, such a subtractive strategy consisting of stopping
further clinical studies are required. the harmful compounds associated with the treatment of OSD has been
shown to be effective in several case series, not only to improve the
6.1.2.3. Tempol. Tempol is a superoxide dismutase mimetic and free ocular surface but also to reduce IOP, probably through reduction of
radical scavenger. When tempol was given subcutaneously by implanted inflammatory reactions within the TM (Batra et al., 2014; Dubrulle et al.,
osmotic mini-pumps (constant infusion for 6 weeks) in mice with 2018). When preventive and subtractive strategies are not feasible, some
unilaterally induced IOP elevation, it was shown to reduce the activation anti-inflammatory options may improve OSD in glaucoma patients.
of NF-κB, which limits the expression of proinflammatory cytokines
including IL-1, IL-2, IFN-γ, and TNF-α in eyes of ocular hypertensive rats 6.3.1. Cyclosporine A
(Yang et al., 2016). Cyclosporine A is an immunomodulatory, anti-inflammatory, and
anti-fibroblastic agent. Its topical formulation is currently indicated for
the treatment of inflammation in dry eye disease. In a prospective
6.1.2.4. Lipoic acid. It was demonstrated that dietary administration of
comparative study in POAG patients, treatment with topical cyclo
the anti-oxidant α-lipoic acid, an organosulfur compound derived from
sporine 0.05%, twice daily for 6 months concurrently with glaucoma
octanoic acid to DBA/2 J mice, it resulted in a significant decrease in
tous eye drops was shown to improve OSD as assessed by Schirmer’s test,
RGC death and a generally decrease in upregulation of specific genes
ocular staining, ocular surface disease index (OSDI), corneal sensations
and proteins related to oxidative stress (Inman et al., 2013).
and corneal sub-basal nerve fiber bundle density (Saini et al., 2015).
This confirms the beneficial effect of topical cyclosporine in the treat
ment of ocular inflammation as shown in dry eye patients, with a good
18
overall safety profile with only mild adverse events (Zhou et al., 2014). between species. Thus there is clearly a need for innovative animal
models such as the microbead occlusion model in non-human primate
6.3.2. Rebamipide (Lambert et al., 2019), or the hyaluronic acid glycidyl methacrylate
Rebamipide, a quinolone derivative, is an ophthalmic solution (HAMA) mouse model (Guo et al., 2018) which seem attractive models.
indicated for the treatment of dry eye disease (Kinoshita et al., 2012). New genetic glaucoma models may also improve the translatability of
This product has anti-inflammatory and anti-oxidant properties and current models (Harada et al., 2019).
induces mucin secretion when applied on the ocular surface (Ohguchi The pathophysiology of glaucoma involves complex inflammatory
et al., 2013). It has been shown to inhibit the increase of TNF-α-induced responses, at various levels with an interaction of various pathways.
IL-6 and IL-8 in a human corneal epithelial cell line (Tanaka et al., Para-inflammation seems necessary in response to various stimuli in
2013). In glaucoma patients treated with BAK-preserved eye drops, order to maintain healthy ocular tissues including the retina, the ante
rebamipide, administered four times daily, resulted in improved corneal rior chamber, and the ocular surface. However, the magnitude of this
barrier function and improved tear break-up time after 2 months para-inflammation is variable and is likely increased during aging (Xu
(Tokuda et al., 2015). et al., 2009). Within the eye, the inflammatory responses are mainly
regulated by glial cells in the retinal/neuronal tissue and by TM cells in
6.3.3. Ketorolac the trabecular meshwork. These cells are essential to maintain tissue
Although the association of nonsteroidal anti-inflammatory drugs reparation and recovery, and to avoid the development of inflammation
and prostaglandins analogues is currently not approved in the treatment with immune cell infiltration. The feedback process to recovery is likely
of glaucoma, one small open-labelled contro-lateral eye controlled impaired in glaucoma where sustained stress is elicited by mechanical,
clinical trial showed that topical ketorolac, a non-selective cyclo vascular and oxidative stress. When this stress is maintained over time, it
oxygenase inhibitor, significantly enhanced the IOP-lowering effect of may result in chronic inflammation, causing TM cell and RGC loss or
prostaglandins analogues (PGAs), including latanoprost, travoprost, and ONH degeneration.. There is also evidence that even at subclinical
bimatoprost in POAG patients (Turan-Vural et al., 2012). Such results levels, inflammation occurs at the ocular surface of glaucoma patients
need to be confirmed in larger double-asked randomized clinical trials on active therapy, resulting in OSD, corneal dysfunction and subcon
but are consistent with other studies and was attributed to inhibiting the junctival fibrosis. The potential effects of severe chronic surface
generation of endogenous prostaglandins that may compete with PGAs inflammation to deeper structures like the trabecular meshwork, the
to improve aqueous outflow facility (Costagliola et al., 2008; Zhu et al., lens or even the retina, remain speculative. However, several arguments
2018). support the detrimental consequences that may be masked by the
IOP-lowering effects of the topical medications, rendering such in
6.3.4. Nutraceuticals teractions very difficult to identify. Therefore, a careful assessment of
Nutraceutical intervention could be a valuable option for OSD in OSD in glaucomatous patients especially when treated with preserved
glaucoma-treated patients. One open-label randomised study showed eyedrops is highly advisable. When suppression or reduction of the
that administration of an oral supplementation of anti-oxidants and compounds responsible for such inflammation is not possible, treating
essential fatty acids for three months led to decreased levels of inflam ocular surface inflammation with anti-inflammatory drugs may be rec
matory cytokines (IL-6 and TNF-α) in tears of POAG patients (Galbi ommended. Control of inflammation to restore a normal immune ho
s-Estrada et al., 2013). In two large open-label studies, administration of meostasis constitutes an attractive therapeutic approach in glaucoma.
an oral supplement containing vitamins, anti-oxidants, minerals, and Various therapeutic targets aimed at suppressing oxidative stress or
omega-3 fatty acids for three or six months showed improvement of dry chronic neuroinflammation are considered promising based on animal
eye signs and symptoms associated with a small but significant glaucoma models. However, interventional studies in humans are still
improvement of IOP in glaucoma patients treated with IOP-lowering eye lacking. Animal experimental glaucoma models have generally sug
drops (Tellez-Vazquez, 2016; Romeo Villadoniga et al., 2018). gested that the inflammatory processes are initiated in early stages of
glaucoma. Therefore, it would be appropriate to treat inflammation
6.4. Treatment of ocular inflammation before filtering surgery early in the development of the disease before the excessive and
intractable cell loss and tissue remodeling abnormalities occur. This
Treating the ocular surface with anti-inflammatory drugs before remains particularly challenging in this slowly developing disease
trabeculectomy may be advisable as initially suggested by Broadway because of the lack of biomarkers of disease progression and chronic
et al. Preoperative 1% fluorometholone eye drops one month before inflammation (Agnifili et al., 2015). A question remains to determine
surgery can improve the ocular surface and the success rate of filtration whether the anti-inflammatory therapy would have to be delivered at
surgery (Broadway et al., 1996). Indomethacin (unpreserved) and flu the TM level to prevent or control IOP increase, at the ONH level, which
orometholone (preserved) eye drops administered one month before is less easily accessible to therapy, or both. Lastly, another unsolved
filtering surgery in glaucomatous patients also reduced subclinical issue would be the dual activity of the targeted inflammatory mediators
conjunctival inflammation as measured by ocular surface HLA-DR and the level of inhibition to restore the inflammatory balance. It is
expression (Baudouin et al., 2002). Recently, ketorolac eye drops questionable whether a complete and uncontrolled inhibition would be
administered for one month in 61 patients with uncontrolled IOP before beneficial. Thus, further research is required and should be encouraged.
surgery were shown to be associated with improved trabeculectomy
outcome in the likelihood of postoperative needling (41% in the placebo Conflicts of interest
group versus 6% in the ketorolac group, and 5% in the fluorometholone
group, p = 0.006) (Breusegem et al., 2010). Christophe Baudouin: Consulting and/or research grants from Aerie,
Alcon, Allergan, Dompe, Horus Pharma, Santen, SIFI, and Théa. Patent
7. Concluding remarks from EyePrim® OPIA.
Miriam Kolko: Speaker, advisor and/or research grants from Théa
In summary, there are consistent findings from animal models and and Santen.
from post-mortem human ONH specimen supporting the role of neuro Stéphane Melik-Parsadaniantz: none.
inflammation in glaucoma. Various mechanisms have been proposed but Elisabeth M. Messmer: Speaker and/or advisor for the following
they cannot be currently translated into clinical science, due to the slow companies: Alcon Pharma GmbH, Dompé, Pharm-Allergan GmbH,
age-related progression of this multifactorial disease where numerous Santen GmbH, Shire, Sun Pharmaceuticals, Théa Pharma GmbH, TRB-
factors interact and also to the inherent difference in eye structure Chemedica, Ursapharm Arzneimittel GmbH, Visufarma
19
Acknowledgements Baudouin, C., Pisella, P.J., Fillacier, K., Goldschild, M., Becquet, F., De Saint Jean, M.,
Béchetoille, A., 1999. Ocular surface inflammatory changes induced by topical
antiglaucoma drugs: human and animal studies. Ophthalmology 106, 556–563.
The authors thank Thierry Radeau for his valuable help in writing Baudouin, C., Nordmann, J.P., Denis, P., Creuzot-Garcher, C., Allaire, C., Trinquand, C.,
and editing the manuscript. 2002. Efficacy of indomethacin 0.1% and fluorometholone 0.1% on conjunctival
Sources of financial assistance: Laboratories Théa for the group of inflammation following chronic application of antiglaucomatous drugs. Graefes
Arch. Clin. Exp. Ophthalmol. 240, 929–935.
authors meetings and for funding editing/proofreading. IHU FORe Baudouin, C., Hamard, P., Liang, H., Creuzot-Garcher, C., Bensoussan, L., Brignole, F.,
SIGHT (ANR-18-IAHU-01) 2004. Conjunctival epithelial cell expression of interleukins and inflammatory
markers in glaucoma patients treated over the long term. Ophthalmology 111,
2186–2192.
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