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.
Conclusions: The findings of this study support a key role for astroglial NF-κB in neuroinflammatory and neurodegenerative outcomes of experimental glaucoma and the potential of this transcriptional regulator pathway as a glial treatment target to provide neuroprotection through immunomodulation. By pointing to a potential treatment strategy targeting the astroglia, these experimental findings are promising for future clinical translation through transgenic applications to improve the treatment of this blinding disease.
Keywords: Astroglia; Glaucoma; IκKβ; NF-κB; Neurodegeneration; Neuroinflammation.