September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Astroglial NF-κB, an Immunomodulatory Treatment Target for Glaucoma
Author Affiliations & Notes
  • Gulgun Tezel
    Ophthalmology, Columbia University, New York, New York, United States
  • Xiangjun Yang
    Ophthalmology, Columbia University, New York, New York, United States
  • Gozde Hondur
    Ophthalmology, Columbia University, New York, New York, United States
  • Footnotes
    Commercial Relationships   Gulgun Tezel, None; Xiangjun Yang, None; Gozde Hondur, None
  • Footnotes
    Support  NIH 1R21EY024105, GRF, and RPB
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2545. doi:
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      Gulgun Tezel, Xiangjun Yang, Gozde Hondur; Astroglial NF-κB, an Immunomodulatory Treatment Target for Glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2545.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Recent experimental data indicated NF-κB as a common regulator of glial neuroinflammation pathways in glaucoma and targeting this transcriptional activator of inflammation as a logical strategy to provide immunomodulation and avoid secondary injury processes. This study aimed to further test astroglial NF-κB to provide immunomodulation/neuroprotection in experimental glaucoma.

Methods : The study employed an astroglia-targeted transgenic mouse model (crossbreds of IκKβ-f/f and GFAP-CreERT2), in which the NF-κB canonical pathway is inactivated by IκKβ deletion specifically in GFAP-expressing astroglia. Intraocular pressure (IOP) elevation was induced by anterior chamber microbead/viscoelastic injections in transgenic mice and transgenic or background controls (C57BL/6J). Transgenic effects on a diverse set of inflammatory responses, including cytokine/chemokine profiles by multiplexed bioassays and glial immunolabeling, were analyzed at 6 weeks of ocular hypertension. To determine whether inhibition of astroglial NF-κB protects neurons from immunogenic injury in experimental glaucoma, retinal ganglion cell and axon counts were analyzed.

Results : Anterior chamber microbead/viscoelastic injections in astroglial IκKβ-deleted mice induced moderate IOP elevation (mean±SD, 22.1±3.6 mmHg) for a period of 6 weeks and exhibited a similar morphology of ocular hypertension-induced neuron loss as in C57BL/6J mice. Including a minimum of 3 mice per group, ocular hypertensive retina and optic nerve in the astroglial IκKβ-deleted mice exhibited approximately four-fold lower ELISA titers of pro-inflammatory cytokines (including TNF-α and IFN-γ) compared to ocular hypertensive controls. Comparison of neuron counts between transgenic and control groups (matched for the IOP-time integral) indicated over 40% less neuron loss in astroglial IκKβ-deleted ocular hypertensive mice (42,932±5,353) than ocular hypertensive controls (34,921±4,384). Also detectable was a decrease in microglial response as assessed by decreased Iba1 immunolabeling in the ocular hypertensive GFAP-IκKβ mice, suggesting the contribution of astroglial NF-κB in astroglia-microglia interactions in neuroinflammation.

Conclusions : Astroglial NF-κB appears to be a promising treatment target to prevent neurodegenerative inflammation in the retina and optic nerve and provide neuroprotection through immunomodulation in experimental glaucoma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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