June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Caspase-8/cFLIP Interaction in the Regulation of Neuroinflammation in 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
  • Qun Zeng
    Ophthalmology, Columbia University, New York, New York, United States
  • Chyuan-Sheng Lin
    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States
  • Footnotes
    Commercial Relationships   Gulgun Tezel None; Xiangjun Yang None; Qun Zeng None; Chyuan-Sheng Lin None
  • Footnotes
    Support  NIH Grants R01EY028153, R01EY033359, P30EY019007, and RPB
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1010. doi:
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      Gulgun Tezel, Xiangjun Yang, Qun Zeng, Chyuan-Sheng Lin; Caspase-8/cFLIP Interaction in the Regulation of Neuroinflammation in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1010.

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

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Abstract

Purpose : Recent in vitro and in vivo studies using pharmacologic or transgenic inhibition of caspase-8 supported cell type-specific processes regulating different fates of RGCs and astroglia during glaucomatous neurodegeneration. We hypothesized that cFLIP, an anti-apoptotic gene target of NF-κB, functions as a molecular switch between caspase-8-mediated cell death/survival/inflammation pathways and regulates cell type-specific caspase-8 functions, such as inflammatory responses of astroglia (highly express cFLIP) vs apoptosis of RGCs (poorly express cFLIP). This study analyzed the outcomes of astroglia-targeting transgenic models on neurodegenerative inflammation in experimental glaucoma for further testing.

Methods : Ocular hypertension was induced by anterior chamber microbead injections in mice with conditional deletion of cFLIP (or cFLIPL to determine isoform-specificity) in astroglia (crossbreds of cFLIPf/f or cFLIPLf/f with GFAP-cre/ERT2) and background controls (cFLIPf/f or cFLIPLf/f). Morphologic and molecular analyses of the retina and optic nerve assessed the distribution of different glial states (by specific marker labeling) and cytokine/chemokine profiles (by multiplex immunoassays). We also analyzed neuron survival (by RGC axon/soma counting) and function (by PERG).

Results : Analyses of retinal whole mounts and optic nerve sections exhibited >four-fold decrease in the number of C3+/TNFα+ astroglia in GFAP/cFLIP (and GFAP/FLIPL) mice compared to their controls at 12-week of ocular hypertension (P<0.001). Similarly, there was >three-fold reduction of pro-inflammatory cytokines (including IL-2, TNF-α, IFN-γ) in samples from ocular hypertensive GFAP/cFLIP (and GFAP/FLIPL) relative to ocular hypertensive controls (n:4; P=0.02). We also detected a greater number of remaining RGCs and axons in ocular hypertensive GFAP/cFLIP and GFAP/cFLIPL mice than controls (23% vs 36% neuron loss; P<0.001).

Conclusions : Our observations support that caspase-8 functions (related to its dead effector domain, scaffold function, or enzymatic activity) are controlled by caspase-8/cFLIP interaction. Deletion of cFLIP (or cFLIPL) in astroglia can prevent/reverse neurodegenerative inflammation by selectively targeting proinflammatory/neurotoxic glia (that are primed for inflammatory caspase-8 functions through TNF-α/TNFR, Fas/FasL, TLRs, and inflammasome) and protect RGCs against inflammatory injury in experimental glaucoma.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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