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

EMBO Molecular Medicine

Florian Sennlaub⁵  Constance Auvynet⁵  Bertrand Calippe⁵  Sophie Lavalette⁵  Lucie Poupel²  Shulong J. Hu⁵  Elisa Dominguez⁵  Serge Camelo⁵  Olivier Levy⁵  Elodie Guyon⁵  Noah Saederup³  Israel F. Charo³  Nico Van Rooijen⁴  Emeline Nandrot⁵  Jean-Louis Bourges¹  Francine Behar-Cohen¹  José-Alain Sahel⁵  Xavier Guillonneau⁵  William Raoul⁵ 

[1] Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique, Paris, France;Inserm UMR_S 945, Laboratoire Immunité et Infection, Paris, France;Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA;Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands;Inserm, U 968, Paris, France

关键词: age‐related macular disease;    chemokines;    monocyte;    neurodegeneration;    neuroinflammation;   

DOI  :  10.1002/emmm.201302692

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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