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Xiangjun Yang, Gozde Hondur, Stan Krajewski, Razqallah Hakem, Gulgun Tezel; Astroglia-Targeted Inhibition of Caspase-8 for Immunomodulation in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2547.
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© ARVO (1962-2015); The Authors (2016-present)
Based on recent in vitro and in vivo studies using pharmacological caspase-8 inhibition, caspase-8 activity is differently processed in retinal ganglion cells (RGCs) and glia (pro-apoptotic or pro-survival/pro-inflammatory), and besides inhibiting apoptosis in RGCs themselves, caspase-8 inhibition in glia can protect RGCs from neurodegenerative inflammation in glaucoma. To further test this hypothesis, this study analyzed the outcomes of astroglia-targeted transgenic inhibition of caspase-8 in experimental glaucoma.
Intraocular pressure (IOP) elevation was induced in transgenic mice (crossbreds of caspase-8 f/f and GFAP-CreERT2) and transgenic or background (C57BL/6J) controls by microbead/viscoelastic injections into the anterior chamber. Following a 6-week ocular hypertensive period, the inflammatory status in the retina and optic nerve was determined by analysis of the glial activation phenotype, cytokine/chemokine profiles, and transcriptional NF-κB activity. The effects of astroglia-targeted caspase-8 deletion on neuron injury was also analyzed by RGC and axon counts in transgenic and control groups matched for the IOP-time integral.
Similar to C57BL/6J controls, anterior chamber microbead/viscoelastic injections in astroglial caspase-8-deleted mice resulted in moderate IOP elevation (21.3±3.6 mmHg). In the ocular hypertensive group of mice with astroglial caspase-8 deletion, the number of GFAP+ astrocytes in the retina and optic nerve was decreased over 30%, and the neuron loss (adjusted to normotensive fellow eyes) was decreased approximately 50% (44,816±4,955) compared to ocular hypertensive C57BL/6J controls (including a minimum of 3 mice per group). However, no prominent alteration was detectable in the counts of glutamine synthethase+ Müller glia, or Iba1+ microglia between transgenic and control groups. Also detected was approximately three-fold lower ELISA titers of the pro-inflammatory cytokines (including TNF-α and IFN-γ) and over two-fold decreased activity of NF-κB in the ocular hypertensive retina and optic nerve of mice with astroglial caspase-8 deletion compared to ocular hypertensive controls.
These findings suggest that targeting the astroglial caspase-8 can provide immunomodulation/neuroprotection in experimental glaucoma by removing the inflammatory glia and preventing the glia-driven neurodegenerative inflammation.
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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