June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Caspase-8-mediated inflammation but not apoptosis drives the development of glaucoma
Author Affiliations & Notes
  • Yinjie Guo
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Maleeka Shrestha
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Ann Marshak-Rothstein
    Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  • Meredith S Gregory-Ksander
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Yinjie Guo, None; Maleeka Shrestha, None; Ann Marshak-Rothstein, None; Meredith Gregory-Ksander, None
  • Footnotes
    Support  NIH Grant R21EY030276
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2350. doi:
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      Yinjie Guo, Maleeka Shrestha, Ann Marshak-Rothstein, Meredith S Gregory-Ksander; Caspase-8-mediated inflammation but not apoptosis drives the development of glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2350.

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

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Abstract

Purpose : Glaucoma is a complex multifactorial disease where apoptosis and inflammation represent two key pathogenic mechanisms. However, the relative contribution of apoptosis versus inflammation in axon degeneration and death of retinal ganglion cells (RGCs) is unknown. We previously demonstrated that Fas-FasL signaling is required for the development of glaucoma. While triggering of the Fas receptor is best known for inducing apoptosis through the activation of caspase-8, activated caspase-8 can also induce the production of pro-inflammatory mediators and caspase-8-mediated inflammation has been linked to the death of RGCs in glaucoma. The recent development of a caspase-8 mutant mouse (Casp8DA/DA) in which a point mutation in the auto-cleavage site blocks caspase-8-mediated apoptosis but does not block caspase-8-mediated inflammation, will allow us for the first time to uncouple the two pathways and definitively determine the extent to which caspase-8-mediated inflammation and/or apoptosis contributes to the death of RGCs in glaucoma.

Methods : Intracameral injection of magnetic microbeads (control: saline) was used to elevate the intraocular pressure (IOP) in Casp8DA/DA mutant mice and WT littermates. IOP was monitored by rebound tonometry twice a week and RGC function was monitored by pattern ERG (pERG). At 4 weeks post microbead injection, RGC density was measured in retinal whole mounts stained with a RGC-specific anti-Brn3a antibody.

Results : Rebound tonometry showed equivalent elevation of IOP in microbead-injected Casp8 DA/DA mutant mice and WT littermates. At 2 weeks post microbead injection, pERG amplitude was significantly decreased in both Casp8DA/DAmutant mice (22.60 ± 1.2 uV at baseline to 16.27 ± 1.0 uV, p<0.05) and WT mice from (21.99 ± 3.1 uV at baseline to 15.27 ± 1.2 uV, p<0.05). At 4 weeks post microbead injection, quantification of RGCs revealed a significant decrease in RGC density in both microbead-injected Casp8DA/DA mutant mice (3359.4 ± 95.1 RGCs/mm2) and WT littermates(3768.4 ± 212.4 RGCs/mm2) when compared to saline-injected WT controls (4428.6 ± 114.0 RGCs/mm2, p<0.05).

Conclusions : Our preliminary results indicate that caspase-8-mediated apoptosis is not required for the death of RGCs in a microbead-induced mouse model of glaucoma, indicating that caspase-8-mediated inflammation, but not apoptosis is the driving force in the development of glaucoma.

This is a 2021 ARVO Annual Meeting abstract.

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