CCR2+ monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice

Authors

  • Florian Sennlaub,

    Corresponding author
    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
    4. Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique, Paris, France
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    • These authors contributed equally to this work.
  • Constance Auvynet,

    1. Inserm, U 968, Paris, France
    2. Inserm UMR_S 945, Laboratoire Immunité et Infection, Paris, France
    3. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 945, Paris, France
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    • These authors contributed equally to this work.
  • Bertrand Calippe,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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    • These authors contributed equally to this work.
  • Sophie Lavalette,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Lucie Poupel,

    1. Inserm UMR_S 945, Laboratoire Immunité et Infection, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 945, Paris, France
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  • Shulong J. Hu,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Elisa Dominguez,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Serge Camelo,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Olivier Levy,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Elodie Guyon,

    1. Inserm, U 968, Paris, France
    2. Inserm UMR_S 945, Laboratoire Immunité et Infection, Paris, France
    3. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 945, Paris, France
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  • Noah Saederup,

    1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
    2. Cardiovascular Research Institute, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Israel F. Charo,

    1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
    2. Cardiovascular Research Institute, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • Nico Van Rooijen,

    1. Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands
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  • Emeline Nandrot,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Jean-Louis Bourges,

    1. Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique, Paris, France
    2. Inserm, UMR_S 872, Centre de Recherche des Cordeliers, Paris, France
    3. Université Paris Descartes, UMR_S 872, Centre de Recherche des Cordeliers, Paris, France
    4. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 872, Paris, France
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  • Francine Behar-Cohen,

    1. Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique, Paris, France
    2. Inserm, UMR_S 872, Centre de Recherche des Cordeliers, Paris, France
    3. Université Paris Descartes, UMR_S 872, Centre de Recherche des Cordeliers, Paris, France
    4. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 872, Paris, France
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  • José-Alain Sahel,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Xavier Guillonneau,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • William Raoul,

    1. Inserm, U 968, Paris, France
    2. UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
    3. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
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  • Christophe Combadiere

    Corresponding author
    1. Inserm UMR_S 945, Laboratoire Immunité et Infection, Paris, France
    2. Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 945, Paris, France
    3. AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service d'Immunologie, Paris, France
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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.

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