September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The value of broad spectrum chemokine inhibitors in modulating microglia/macrophage-mediated inflammation in a model of atrophic AMD
Author Affiliations & Notes
  • Matt Rutar
    The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
  • Nilisha Fernando
    The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
  • Riccardo Natoli
    The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
    ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
  • Jan Provis
    The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
    ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
  • Krisztina Valter
    The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
    ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
  • Footnotes
    Commercial Relationships   Matt Rutar, None; Nilisha Fernando, None; Riccardo Natoli, None; Jan Provis, None; Krisztina Valter, None
  • Footnotes
    Support  The Ophthalmic Research Institute of Australia New Investigator Grant, The National Health and Medical Research Council Project Grant
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Matt Rutar, Nilisha Fernando, Riccardo Natoli, Jan Provis, Krisztina Valter; The value of broad spectrum chemokine inhibitors in modulating microglia/macrophage-mediated inflammation in a model of atrophic AMD. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Abstract

Purpose : Macrophage recruitment and activation is implicated in pathogenesis of retinal diseases such as atrophic AMD, where they accumulate amongst the ONL and subretinal space. Such recruitment is aided by the expression of chemokines, which furnish these cells with directional cues that augment their migration to areas of retinal injury. While these qualities make chemokines a potential therapeutic target in curtailing retinal inflammation, their wide variety and signalling redundancy pose challenges to broadly modulating their activity. Here, we examine the efficacy of the broad spectrum chemokine inhibitor (BSCI) NR58-3.14.3 – a suppressor of Ccl- and Cxcl- pathways – in reducing macrophage activity and photoreceptor death, using a light-induced model of outer-retinal atrophy and inflammation.

Methods : Photooxidative damage was induced in SD rats via exposure to 1000lx light for 24hrs, which were then euthanized at 0 or 7 days post-exposure (n=12 for each group). Prior to damage, NR58-3.14.3 was injected intravitreally. Retinas were harvested and evaluated for the effect of NR58-3.14.3 on the recruitment and cytokine expression profile of subretinal macrophages (FACS, qPCR, Immunohistochemistry), as well as photoreceptor degeneration (TUNEL). One-way ANOVA was used for statistics.

Results : Injection of NR58-3.14.3 reduced the accumulation of subretinal macrophages following exposure to light damage, at both 0 and 7 days post-exposure time-points , compared to PBS-injected controls <span style="line-height:20.8px">(P<0.05)</span>. NR58-3.14.3 also reduced the up-regulation of inflammatory markers including of Il6, Ccl3 and Ccl4 in recruited macrophages (P<0.05), which are promoters of their pathogenic activity in the retina. Finally, NR58-3.14.3 injected retinas displayed markedly reduced photoreceptor death following light damage, at both 0 and 7 days post-exposure (P<0.05).

Conclusions : Our findings indicate that NR58-3.14.3 is effective in inhibiting macrophage activity and cell death in light damage, and thus illustrates the potential of BSCIs as novel therapeutic agents in thwarting retinal inflammation. Although BSCIs may not be appropriate for all retinal inflammatory conditions, our results suggest that they may be beneficial for retinal dystrophies in which chemokine expression and subretinal macrophage recruitment are implicated, such as advanced AMD.

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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