July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Neuroprotective outcomes of immunomodulation by transgenic inhibition of astroglial NF-κB may involve increased glial metabolic support
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
  • Jian Cai
    Medicine, University of Louisville, Louisville, Kentucky, United States
  • Jon B Klein
    Medicine, University of Louisville, Louisville, Kentucky, United States
  • Footnotes
    Commercial Relationships   Gulgun Tezel, None; Xiangjun Yang, None; Jian Cai, None; Jon Klein, None
  • Footnotes
    Support  NIH Grant EY024105, GRF, and RPB
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 6140. doi:
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      Gulgun Tezel, Xiangjun Yang, Jian Cai, Jon B Klein; Neuroprotective outcomes of immunomodulation by transgenic inhibition of astroglial NF-κB may involve increased glial metabolic support. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6140.

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

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Abstract

Purpose : Our recent studies targeted glial NF-κB (a transcriptional activator of inflammation) by cre/lox-based IκKβ deletion and reported immunomodulatory and neuroprotective outcomes in experimental glaucoma. This extension study aimed to further analyze structural and functional neuroprotection, and glia-specific molecular responses.

Methods : To model glaucoma, IOP elevation was induced by anterior chamber microbead/viscoelastic injections in transgenic (crossbreds of IκKβ-f/f and GFAP-CreERT2) and WT (C57BL/6J) mice. Transgenic effects on neuron survival and function (by RGC/axon counts and PERG) and glial inflammatory phenotype (by glial morphology/GFAP/Iba labeling, and cytokine/chemokine profiles) were determined at 12 weeks of ocular hypertension. In addition, we isolated retina and optic nerve head astroglia (by immunomagnetic cell selection) for isotope labeling-based quantitative LC-MS/MS analysis.

Results : Comparison of neuron counts and PERG amplitude indicated over 40% less neuron loss in astroglial IκKβ-deleted versus WT ocular hypertensive mice (matched for the IOP-time integral). Parallel to morphological alterations of glia, astroglial deletion of IκKβ resulted in approximately four-fold lower ELISA titers of pro-inflammatory cytokines (including TNF-α and IFN-γ). Based on IPA analysis of astroglia-specific proteomics datasets (with false discovery rate of <1%), transgenic effects included over two-fold down-regulation of various molecules linked to inflammation-promoting pathways. Moreover, our high-throughput data indicated a significant up-regulation (p<0.05) of a number of molecules involved in astroglial glycogenesis, glycogen breakdown, and lactate/pyruvate generation for monocarboxylate export in ocular hypertensive mice with astroglial IκKβ deletion.

Conclusions : Astroglia-targeted transgenic inhibition of neuroinflammation in experimental glaucoma reduces neurodegeneration at different neuronal compartments, including RGC somas and axons. Perhaps due to decreased energy need of glial cells themselves, neuroprotective outcomes may also include an additional component of improved glial neurosupport by increased supplement of energy substrates to relieve neuronal energy insufficiency. These findings stimulate further studies of neuron-glia interactions to develop glia-targeting treatments for immunomodulation and neuroprotection in glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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