title: Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age-related macular degeneration.
abstract: Physiologically, the retinal pigment epithelium (RPE) expresses immunosuppressive signals such as FAS ligand (FASL), which prevents the accumulation of leukocytes in the subretinal space. Age-related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and chronic accumulation of mononuclear phagocytes (MPs). We show that subretinal MPs in AMD patients accumulate on the RPE and express high levels of APOE. MPs of Cx3cr1(-/-) mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization similarly express high levels of APOE. ApoE deletion in Cx3cr1(-/-) mice prevents pathogenic age- and stress-induced subretinal MP accumulation. We demonstrate that increased APOE levels induce IL-6 in MPs via the activation of the TLR2-CD14-dependent innate immunity receptor cluster. IL-6 in turn represses RPE FasL expression and prolongs subretinal MP survival. This mechanism may account, in part, for the MP accumulation observed in Cx3cr1(-/-) mice. Our results underline the inflammatory role of APOE in sterile inflammation in the immunosuppressive subretinal space. They provide rationale for the implication of IL-6 in AMD and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD.
authors.affiliation: INSERM, 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Levy
authors.affiliation: INSERM, 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Calippe
authors.affiliation: INSERM, 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavalette
authors.affiliation: INSERM, 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.
authors.forename: Shulong J
authors.initials: SJ
authors.lastname: Hu
authors.affiliation: INSERM, 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.
authors.forename: William
authors.initials: W
authors.lastname: Raoul
authors.affiliation: INSERM, 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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dominguez
authors.affiliation: INSERM, 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Housset
authors.affiliation: INSERM, 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.affiliation: INSERM, 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.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, 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 CEA DSV I²BM Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France CNRS CEA URA 2210, Fontenay-aux-Roses, France.
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06 CR7 Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM U1135 CIMI-Paris, Paris, France CNRS ERL 8255 CIMI-Paris, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadiere
authors.affiliation: INSERM, 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: INSERM, 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 florian.sennlaub@inserm.fr.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival; D020256:Choroidal Neovascularization; D053222:Fas Ligand Protein / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010586:Phagocytes / Q000166:cytology* / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D055213:Retinal Pigment Epithelium / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D053222:Fas Ligand Protein; D015850:Interleukin-6; D019707:Receptors, Chemokine
keywords: age‐related macular degeneration; apolipoprotein E; interleukin 6; mononuclear phagocyte; neuroinflammation