Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina

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Date
2017-02-20
Authors
Roche, Sarah L.
Wyse-Jackson, Alice C.
Ruiz-Lopez, Ana M.
Byrne, Ashleigh M.
Cotter, Thomas G.
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Nature Publishing Group
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Abstract
Retinitis pigmentosa (RP) encompasses a group of retinal diseases resulting in photoreceptor loss and blindness. We have previously shown in the rd10 mouse model of RP, that rd10 microglia drive degeneration of viable neurons. Norgestrel, a progesterone analogue, primes viable neurons against potential microglial damage. In the current study we wished to investigate this neuroprotective effect further. We were particularly interested in the role of fractalkine-CX3CR1 signaling, previously shown to mediate photoreceptor-microglia crosstalk and promote survival in the rd10 retina. Norgestrel upregulates fractalkine-CX3CR1 signaling in the rd10 retina, coinciding with photoreceptor survival. We show that Norgestrel-treated photoreceptor-like cells, 661Ws, and C57 explants modulate rd10 microglial activity in co-culture, resulting in increased photoreceptor survival. Assessment of Norgestrel’s neuroprotective effects when fractalkine was knocked-down in 661 W cells and release of fractalkine was reduced in rd10 explants confirms a crucial role for fractalkine-CX3CR1 signaling in Norgestrel-mediated neuroprotection. To further understand the role of fractalkine in neuroprotection, we assessed the release of 40 cytokines in fractalkine-treated rd10 microglia and explants. In both cases, treatment with fractalkine reduced a variety of pro-inflammatory cytokines. These findings further our understanding of Norgestrel’s neuroprotective properties, capable of modulating harmful microglial activity indirectly through photoreceptors, leading to increased neuroprotection.
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Retinitis pigmentosa (RP) , Microglia , Retinal diseases
Citation
Roche, S. L., Wyse-Jackson, A. C., Ruiz-Lopez, A. M., Byrne, A. M. and Cotter, T. G. (2017) 'Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina', Scientific Reports, 7, pp. 43067. doi:10.1038/srep43067