title: Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina.
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.
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Roche
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Wyse-Jackson
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ruiz-Lopez
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Ashleigh M
authors.initials: AM
authors.lastname: Byrne
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism*; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D016207:Cytokines; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D000066829:Neuroprotection; D009644:Norgestrel / Q000494:pharmacology*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D009644:Norgestrel; D011374:Progesterone