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The broad-spectrum chemokine inhibitor NR58-3.14.3 modulates macrophage-mediated inflammation in the diseased retina

Fernando, Nilisha; Natoli, Riccardo; Valter, Krisztina; Provis, Jan; Rutar, Matt

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Background The activity of macrophages is implicated in the progression of retinal pathologies such as atrophic age-related macular degeneration (AMD), where they accumulate among the photoreceptor layer and subretinal space. This process is aided by the local 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...[Show more]

dc.contributor.authorFernando, Nilisha
dc.contributor.authorNatoli, Riccardo
dc.contributor.authorValter, Krisztina
dc.contributor.authorProvis, Jan
dc.contributor.authorRutar, Matt
dc.date.accessioned2016-02-26T04:02:10Z
dc.date.available2016-02-26T04:02:10Z
dc.identifier.citationJournal of Neuroinflammation. 2016 Feb 24;13(1):47
dc.identifier.urihttp://hdl.handle.net/1885/99589
dc.description.abstractBackground The activity of macrophages is implicated in the progression of retinal pathologies such as atrophic age-related macular degeneration (AMD), where they accumulate among the photoreceptor layer and subretinal space. This process is aided by the local 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 damaging retinal inflammation, their wide variety and signalling redundancy pose challenges in broadly modulating their activity. Here, we examine the efficacy of the broad-spectrum chemokine inhibitor NR58-3.14.3—a suppressor of Ccl- and Cxcl- chemokine pathways—in suppressing macrophage activity and photoreceptor death, using a light-induced model of outer retinal atrophy and inflammation. Methods Photo-oxidative damage was induced in SD rats via exposure to 1000 lux of light for 24 h, after which animals were euthanized at 0- or 7-day post-exposure time points. Prior to damage, NR58-3.14.3 was injected intravitreally. Retinas were harvested and evaluated for the effect of NR58-3.14.3 on subretinal macrophage accumulation and cytokine expression profile, as well as photoreceptor degeneration. Results We report that intravitreal administration of NR58-3.14.3 reduces the accumulation of macrophages in the outer retina following exposure to light damage, at both 0- and 7-day post-exposure time points. Injection of NR58-3.14.3 also reduced the up-regulation of inflammatory markers including of Il6, Ccl3, and Ccl4 in infiltrating macrophages, 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. Conclusions Our findings indicate that NR58-3.14.3 is effective in inhibiting subretinal macrophage accumulation in light-induced retinal degeneration and illustrate the potential of broad-spectrum chemokine inhibitors as novel therapeutic agents in thwarting retinal inflammation. Although broad-spectrum chemokine inhibitors 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 accumulation are implicated, such as advanced AMD.
dc.publisherBioMed Central
dc.rights© 2016 Fernando et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.sourceJournal of Neuroinflammation
dc.subjectbroad-spectrum chemokine inhibitor NR58-3.14.3
dc.subjectdiseased retina
dc.subjectmacrophage-mediated inflammation
dc.titleThe broad-spectrum chemokine inhibitor NR58-3.14.3 modulates macrophage-mediated inflammation in the diseased retina
dc.typeJournal article
dc.language.rfc3066en
dc.rights.holderFernando et al.
local.identifier.citationvolume13
dc.date.issued2016-02-24
local.identifier.ariespublicationU3488905xPUB11612
local.type.statusPublished Version
local.contributor.affiliationFernando,Nilisha, The John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationNatoli, Riccardo, The John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationValter, Krisztina, The John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationProvis, Jan, The John Curtin School of Medical Research, The Australian National University
local.contributor.affiliationRutar, Matt, The John Curtin School of Medical Research, The Australian National University
local.identifier.doi10.1186/s12974-016-0514-x
dc.date.updated2016-02-24T17:02:26Z
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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