July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Fas signaling triggers glial-mediated neuroinflammation in glaucoma
Author Affiliations & Notes
  • Meredith S Gregory-Ksander
    Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Wennan Lu
    Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Claire H Mitchell
    Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Andrew Kocab
    ONL Therapeutics, Ann Arbor, Michigan, United States
  • David N Zacks
    Kellog Eye Center, University of Michigan, Ann Arbor, Michigan, United States
  • Anitha Krishnan
    Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Meredith Gregory-Ksander, ONL Therapeutics (F); Wennan Lu, None; Claire Mitchell, None; Andrew Kocab, ONL Therapeutics (E); David Zacks, ONL Therapeutics (I), ONL Therapeutics (P), ONL Therapeutics (C); Anitha Krishnan, None
  • Footnotes
    Support  NIH Grant EY016145, ONL Therapeutics
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2257. doi:https://doi.org/
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    • Get Citation

      Meredith S Gregory-Ksander, Wennan Lu, Claire H Mitchell, Andrew Kocab, David N Zacks, Anitha Krishnan; Fas signaling triggers glial-mediated neuroinflammation in glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2257. doi: https://doi.org/.

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

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Abstract

Purpose : Our laboratory demonstrated previously that inhibiting Fas activation in chronic and inducible models of glaucoma prevents death of retinal ganglion cells (RGCs) and loss of axons. Although best known for its apoptotic function, Fas signaling can also trigger inflammatory pathways and in glaucoma, glial activation and inflammation has been linked to axon damage and death of RGCs. Herein, we used genetic and pharmacologic methods to inhibit Fas activation and examined the role of Fas signaling in glial activation and inflammation in the microbead-induced mouse model of glaucoma.

Methods : Intracameral injection of microbeads (control: saline-only) was used to elevate intraocular pressure (IOP) in two groups of mice: (i) WT B6 and Fas-deficient (lpr) mice and (ii) WT B6 mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2μg/1μl) (control: vehicle only). The IOP was monitored by rebound tonometry. Mice were euthanized at 7 and 28 days post microbead injection and the ONH and retina were processed for: (i) qPCR, (ii) immunostaining, and (iii) RGC and axon counts. In vitro, primary cultures of mouse ONH astrocytes were incubated with Fas ligand expressing microvesicles and cell survival and induction of inflammatory genes was examined.

Results : Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. However, Fas deficiency or treatment with ONL1204 significantly reduced death of RGCs and loss of axons when compared to saline controls. At 7 days post microbead injection, qPCR analysis of WT ONHs revealed a significant induction of inflammatory genes (IL-1β, TNFα, and MCP1) that was absent in Fas-deficient mice. In vitro, Fas activation of primary mouse ONH astrocytes induced inflammatory genes (IL-1β and TNFα), but failed to induce apoptosis. At 28 days post microbead injection, confocal analysis and qPCR of the retina demonstrated that Fas inhibition abrogated microglia activation (Iba1 and CD11b staining of retinal whole mounts) and induction of inflammatory genes (TNFα, IL-1β, IL-6, MCP1, MIP1α, and MIP2) in the retina as well.

Conclusions : These results (i) demonstrate Fas is required for death of RGCs and loss of axons in glaucoma and (ii) implicate Fas activation is a trigger of glial-mediated neuroinflammation. In particular, our data indicate astrocyte-mediated neuroinflammation in the ONH is triggered by Fas activation during the development of glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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