June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Neutralization of IFNAR1 prevents histone deacetylase inhibitor induced retinal pigment epithelium cell death
Author Affiliations & Notes
  • kyung sik jung
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Kabhilan Mohan
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Subhash Prajapati
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Sushil Kumar Dubey
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Dingyuan Lou
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Jacob Roney
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Jennifer Brown
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Mark Ellsworth Kleinman
    Ophthalmology, University of Kentucky, Lexington, Kentucky, United States
  • Footnotes
    Commercial Relationships   kyung sik jung, None; Kabhilan Mohan, None; Subhash Prajapati, None; Sushil Dubey, None; Dingyuan Lou, None; Jacob Roney, None; Jennifer Brown, None; Mark Kleinman, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1987. doi:
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      kyung sik jung, Kabhilan Mohan, Subhash Prajapati, Sushil Kumar Dubey, Dingyuan Lou, Jacob Roney, Jennifer Brown, Mark Ellsworth Kleinman; Neutralization of IFNAR1 prevents histone deacetylase inhibitor induced retinal pigment epithelium cell death. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1987.

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

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Abstract

Purpose : We have previously demonstrated that Class I/II histone deacetylase inhibition (HDACi) increased widespread pro-inflammatory gene expression and cell death in the retinal pigment epithelium (RPE). These data also identified interferon related genes which are similarly elevated in RPE from eyes with age-related macular degeneration (IFNb1/CXCL9/10). Here, we studied the Type I interferon (IFN) response during in vitro and in vivo models of HDACi and evaluated the therapeutic potential of pharmacologic blockade of the Type I IFN receptor, IFNAR1.

Methods : Wild-type (Wt) C57BL/6J and Ifnar1-/- (both from Jackson Labs) mouse eyes were imaged by fundus photography 7 days after intravitreous injection of various HDACi (MS-275 (1 µg/µl), MGCD0103 (1 µg/µl), trichostatin-A (TSA, 0.5 µg/µl) or vehicle (DMSO), n=5 per group). Mouse RPE isolates were treated with TSA (0.1/0.5 µM) and analyzed by qPCR for expression of Type I IFNs. Validated short-interfering RNAs (siRNAs, 17+2 nt-cholesterol) and a neutralizing antibody (R&D Systems, AF3039) targeting IFNAR1 were tested in our in vivo model of HDACi induced RPE toxicity. Statistical analyses were performed by Mann-Whitney U or Fisher’s exact tests.

Results : Type I IFN levels were significantly increased in mouse RPE isolates after treatment with TSA (0.1/0.5 µM, p<0.05). In Ifnar-/- mice, we observed no detectable RPE toxicity after intravitreous administration of class I/II HDACi (TSA, MS-275, MGCD0103) compared to significant RPE atrophy in Wt mice (Figure 1A/B/E, color fundus imaging; ZO-1 immunofluorescence, p<0.01). Pharmacologic rescue with pretreatment of anti-IFNAR1 neutralizing antibody or Ifnar1 siRNA significantly decreased HDACi induced RPE degeneration compared to controls (Figure C/D/E, p<0.05).

Conclusions : A significant Type I IFN response was detected with treatment of Class I/II HDACi in RPE. Genetic ablation and pharmacologic inhibition of the Type I IFN receptor, Ifnar1, significantly diminished RPE toxicity and cell death in vivo. These data and others suggest a potential therapeutic role for IFNAR1 inhibition in advanced dry AMD, and future studies will be directed towards understanding the downstream effects of Type I IFN neutralization in RPE.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Figure. Ifnar1 decreased TSA-treated RPE toxicity.

Figure. Ifnar1 decreased TSA-treated RPE toxicity.

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