title: CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice.
abstract: Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2(+) inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2(+) monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD.
authors.affiliation: Inserm, U 968, Paris, France; UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France; Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: Constance
authors.initials: C
authors.lastname: Auvynet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Calippe
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavalette
authors.forename: Lucie
authors.initials: L
authors.lastname: Poupel
authors.forename: Shulong J
authors.initials: SJ
authors.lastname: Hu
authors.forename: Elisa
authors.initials: E
authors.lastname: Dominguez
authors.forename: Serge
authors.initials: S
authors.lastname: Camelo
authors.forename: Olivier
authors.initials: O
authors.lastname: Levy
authors.forename: Elodie
authors.initials: E
authors.lastname: Guyon
authors.forename: Noah
authors.initials: N
authors.lastname: Saederup
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Nico Van
authors.initials: NV
authors.lastname: Rooijen
authors.forename: Emeline
authors.initials: E
authors.lastname: Nandrot
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bourges
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.forename: William
authors.initials: W
authors.lastname: Raoul
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadiere
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D020556:Neutrophil Infiltration; D020419:Photoreceptor Cells, Vertebrate / Q000276:immunology*; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine
keywords: age-related macular disease; chemokines; monocyte; neurodegeneration; neuroinflammation