Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Abstract

Background: Glia-driven neuroinflammation promotes neuron injury in glaucoma that is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness. Although therapeutic modulation of neuroinflammation is increasingly viewed as a logical strategy to avoid inflammatory neurotoxicity in glaucoma, current understanding of the molecular regulation of neuroinflammation is incomplete, and the molecular targets for immunomodulation remains unknown. Growing datasets pointed to nuclear factor-kappaB (NF-κB), a key transcriptional activator of inflammation, which was identified to be most affected in glaucomatous astroglia. Using a cell type-specific experimental approach, this study aimed to determine the value of astroglial NF-κB as a potential treatment target for immunomodulation in experimental mouse glaucoma. Methods: Neuroinflammatory and neurodegenerative outcomes of experimental glaucoma were comparatively analyzed in mice with or without cre/lox-based conditional deletion of astroglial IκKβ, which is the main activating kinase involved in IκB degradation through the canonical pathway of NF-κB activation. Glial responses and the inflammatory status of the retina and optic nerve were analyzed by cell morphology and cytokine profiling, and neuron structure and function were analyzed by counting retinal ganglion cell (RGC) axons and somas and recording pattern electroretinography (PERG) responses. Results: Analysis of glial inflammatory responses showed immunomodulatory outcomes of the conditional transgenic deletion of IκKβ in astroglia. Various pro-inflammatory cytokines known to be transcriptional targets for NF-κB exhibited decreased production in IκKβ-deleted astroglia, which included TNF-α that can induce RGC apoptosis and axon degeneration during glaucomatous neurodegeneration. Indeed, transgenic modulation of inflammatory responses by astroglial IκKβ deletion reduced neurodegeneration at different neuronal compartments, including both RGC axons and somas, and protected PERG responses.

The Role of Neuroinflammation in Glaucoma: An Update on Molecular Mechanisms and New Therapeutic Options

“…The astroglial NF-κB was evaluated as a possible treatment target for the modulation of immune response in an experimental transgenic glaucoma mouse with deletion of IkappaB kinase beta (IκKβ) in astroglial cells ( 59 ). The study showed a reduction of the increase in proinflammatory cytokines (in particular TNF-α) with consequent protection of axon from degeneration and RGCs from apoptosis, as demonstrated also by pattern electroretinogram (PERG) data.…”

Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects

“…Resembling the microglial factors that can stimulate the phenotypic conversion of astrocytes, reactive astrocytes via nuclear factor-kappa B (NF-κB)-regulated cytokines can shape microglia responses as well [192]. As of note on the simplified categorization of glial phenotypes, astrocytes and microglia may, in fact, simultaneously present multiple reactive profiles that vary spatially and temporally.…”

“…Oxidative stress may also incite complement dysregulation in glaucoma [197]. Moreover, NF-κB that regulates glia-driven neuroinflammation [129,192] is a redox-sensitive transcription factor. Indeed, antioxidant treatment limited NF-κB activation and proinflammatory cytokine production in the ocular hypertensive rat retina and optic nerve [91].…”

“…Evidently, this proapoptotic cytokine secreted from reactive glia induces RGC apoptosis, oligodendrocyte death, and axon degeneration through TNFR1 signaling in in vitro [124] and in vivo models [103,147,203,204]. Proinflammatory activities of TNFα/TNFR1 signaling is considerably stronger, as downstream NF-κB activation and transcription of other immune mediators may feed into a vicious cycle [88,109,129,192]. Not only TNFα [124,147], but also FasL, secreted by reactive glia, may induce RGC loss by binding Fas receptor from the same family of receptors [126].…”

Understanding immunotherapy and its management

“…Immunotherapy doesn't take a shot by any stretch of the imagination. Cost is likewise an issue in a portion of the cases [7][8][9][10][11][12][13][14][15]. To prepare a questionnaire for doctors…”