Inhibition of Astroglial Nf-Kappab Pathway Provides Neuroprotection Against Optic Neuropathy in Glaucoma
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.
- 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
- 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
- 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
- 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
- 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