Jawad Muayad

Background: Glaucoma is a group of eye conditions that damage the optic nerve and is a leading cause of blindness in the United States.¹ It is known as the “silent thief of sight” due to its slow and irreversible damage to the eyes before any noticeable vision loss.¹ The most prominent risk factor for glaucoma is increased intraocular pressure (IOP), which damages the optic nerve by pushing on the retinal ganglion cells (RGCs) and their axons.² Neuroinflammation is another key process in glaucoma, but its precise role is not yet fully understood.² Because neuroinflammation has been observed in glaucoma with increased IOP, understanding neuroinflammation’s role in glaucoma may lead to targeted therapeutics.²

Objective: This narrative review investigates the mechanisms of glaucoma induced by neuroinflammation.

Search Methods: An online search was conducted in the PubMed database from 2017 to 2023 using the following keywords: “glaucoma,” “neuroinflammation,” “mechanism,” and “astrocytes.”

Results: Numerous studies have demonstrated that inhibiting neuroinflammatory reactive astrocytes can prevent the death of RGCs.² RGC death is caused by both neuronal injury and the presence of reactive astrocytes, thus making astroglial cells a potential target for combating neuroinflammation in glaucoma.² One mechanism by which astrocytes induce neuroinflammation is through initiating Fas signaling, which leads to the activation of apoptotic and inflammatory pathways.³ FasL-Fas signaling is crucial for axon degeneration and RGC death in both chronic and inducible mouse models of glaucoma.³ Treatment with ONL1204, a Fas receptor antagonist, significantly reduced RGC death and loss of axons in microbead-injected WT mice compared to vehicle-treated controls.³ Additionally, CD95 recruits the adaptor protein Fas-associated death domain (FADD), promoting the induction of the apoptotic program.⁴ Degradation of CD95 induced by FADD promotes the pro-inflammatory NF-κB signaling pathway, resulting in the production of cytokines that recruit natural killer (NK) cells.⁴ Inhibition of the NF-κB transcription factor Relish in astrocytes induced by proteotoxic stress in neurons decreases neurodegeneration.⁴  Given this finding, a study investigated the potential of astroglial NF-κB as a target for immunomodulation in experimental mouse glaucoma.⁵ The study analyzed neuroinflammatory and neurodegenerative outcomes in mice with or without conditional deletion of astroglial IκKβ, which activates NF-κB.⁵ Neuron structure and function were assessed by counting RGCs and recording pattern electroretinography (PERG) responses.⁵ The results revealed that the conditional transgenic deletion of IκKβ in astroglia had immunomodulatory effects, as various pro-inflammatory cytokines known to be transcriptional targets for NF-κB showed decreased production, and reduced neuroinflammation and neurodegeneration, decreasing the loss of RGC axons.⁵

Conclusion: Targeting astroglial cells and the NF-κB signaling pathway can be a promising therapeutic approach for combating neuroinflammation and preventing RGC death in glaucoma. Further research is needed to determine the efficacy and safety of such treatments in humans.

Works Cited:

1.  Nida EK, Bekele S, Geurts L, Vanden Abeele V. Acceptance of a Smartphone-Based Visual Field Screening Platform for Glaucoma: Pre-Post Study. JMIR Form Res. 2021;5(9):e26602. Published 2021 Sep 17. doi:10.2196/26602
2. Guttenplan KA, Stafford BK, El-Danaf RN, et al. Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury. Cell Rep. 2020;31(12):107776. doi:10.1016/j.celrep.2020.107776
3. Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflammation. 2019;16(1):184. Published 2019 Sep 30. doi:10.1186/s12974-019-1576-3
4. Guégan JP, Pollet J, Ginestier C, Charafe-Jauffret E, Peter ME, Legembre P. CD95/Fas suppresses NF-κB activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism. iScience. 2021;24(12):103538. Published 2021 Dec 1. doi:10.1016/j.isci.2021.103538
5. Yang X, Zeng Q, Barış M, Tezel G. Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma. J Neuroinflammation. 2020;17(1):252. Published 2020 Aug 28. doi:10.1186/s12974-020-01930-1