title: Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration.
abstract: Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Shulong J
authors.initials: SJ
authors.lastname: Hu
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Calippe
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Sophie
authors.identifier: http://orcid.org/0000-0001-5029-2724
authors.initials: S
authors.lastname: Lavalette
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Roubeix
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Fadoua
authors.initials: F
authors.lastname: Montassar
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Housset
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Levy
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris F-75013, France, and.
authors.forename: Cecile
authors.initials: C
authors.lastname: Delarasse
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU ViewMaintain, INSERM-DHOS CIC 1423, Paris, F-75012, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU ViewMaintain, INSERM-DHOS CIC 1423, Paris, F-75012, France.
authors.forename: José-Alain
authors.identifier: http://orcid.org/0000-0002-4831-1153
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.affiliation: INSERM, U 968, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 06, UMR S 968, Institut de la Vision, Paris, F-75012, France, CNRS, UMR 7210, Paris, F-75012, France, xavier.guillonneau@inserm.fr.
authors.forename: Xavier
authors.identifier: http://orcid.org/0000-0001-7379-3935
authors.initials: X
authors.lastname: Guillonneau
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018920:Coculture Techniques; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012157:Mononuclear Phagocyte System / Q000378:metabolism* / Q000473:pathology; D010586:Phagocytes / Q000378:metabolism / Q000473:pathology; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D019707:Receptors, Chemokine / Q000172:deficiency*; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C546469:P2rx7 protein, mouse; D019707:Receptors, Chemokine; D058486:Receptors, Purinergic P2X7
keywords: IL-1; P2RX7; inflammasome; monocytes; retina