Progesterone attenuates microglial-driven retinal degeneration and stimulates protective Fractalkine-CX3CR1 signaling

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dc.contributor.authorRoche, Sarah L.
dc.contributor.authorWyse-Jackson, Alice C.
dc.contributor.authorGomez-Vicente, Violeta
dc.contributor.authorLax, Pedro
dc.contributor.authorRuiz-Lopez, Ana M.
dc.contributor.authorByrne, Ashleigh M.
dc.contributor.authorCuenca, Nicolas
dc.contributor.authorCotter, Thomas G.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderFighting Blindness Irelanden
dc.date.accessioned2016-11-10T12:42:58Z
dc.date.available2016-11-10T12:42:58Z
dc.date.issued2016-11-04
dc.date.updated2016-11-10T12:16:04Z
dc.description.abstractRetinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue ‘Norgestrel’ is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel’s neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.en
dc.description.sponsorshipScience Foundation Ireland (SFI 13/IA/1783); Fighting Blindness Ireland (FB13COT)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide0165197
dc.identifier.citationRoche, Sarah L., Wyse-Jackson, Alice C., Gomez-Vicente, Violeta, Lax, Pedro, Ruiz-Lopez, Ana M, Byrne, Ashleigh M., Cuenca, Nicolas, Cotter, Thomas G. (2016) 'Progesterone attenuates microglial-driven retinal degeneration and stimulates protective Fractalkine-CX3CR1 signaling', Plos One, 11(11), e0165197 (27pp). doi: 10.1371/journal.pone.0165197en
dc.identifier.doi10.1371/journal.pone.0165197
dc.identifier.endpagee0165197-27en
dc.identifier.issn1932-6203
dc.identifier.issued11en
dc.identifier.journaltitlePlos Oneen
dc.identifier.startpagee0165197-1en
dc.identifier.urihttps://hdl.handle.net/10468/3263
dc.identifier.volume11en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.rights© 2016 Roche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectRetinitis pigmentosa (RP)en
dc.subjectRetinal degenerationen
dc.subjectMicroglial cellsen
dc.subjectRetinaen
dc.subjectPhotoreceptorsen
dc.subjectDieten
dc.subjectCell deathen
dc.subjectMouse modelsen
dc.subjectNeuronal deathen
dc.subjectProgesteroneen
dc.titleProgesterone attenuates microglial-driven retinal degeneration and stimulates protective Fractalkine-CX3CR1 signalingen
dc.typeArticle (peer-reviewed)en
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