Journal Article

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

Levy, Olivier, Dominguez, Elisa, Sennlaub, Florian, Lavalette, Sophie, Auvynet, Constance, Raoul, William, Guyon, Elodie, Rooijen, Nico Van, Guillonneau, Xavier, Behar‐Cohen, Francine, Poupel, Lucie, Calippe, Bertrand, Camelo, Serge, Bourges, Jean‐Louis, Charo, Israel F., Sahel, José‐Alain, Hu, Shulong J., Nandrot, Emeline, Saederup, Noah, Combadiere, Christophe

2013

Overview

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. Graphical Abstract The eyes of patients with atrophic AMD feature high CCL2 and CCR2 + monocytes. This is modeled in Cx3cr1 KO mice in which Ccl2 and Ccr2 deletion, CCR2 inhibition and monocyte depletion diminished subretinal inflammation and photoreceptor degeneration.

• Publisher: Nature Publishing Group UK,Wiley Open Access,Blackwell Publishing Ltd,Springer Nature
• Subject: age‐related macular disease / Animals / Chemokine CCL2 - immunology / chemokines / CX3C Chemokine Receptor 1 / Female / Human health and pathology / Humans / Immunology / Inflammation - genetics / Inflammation - immunology / Life Sciences / Macular Degeneration - genetics / Macular Degeneration - immunology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / monocyte / Monocytes - immunology / neurodegeneration / neuroinflammation / Neutrophil Infiltration / Photoreceptor Cells, Vertebrate - immunology / Receptors, CCR2 - genetics / Receptors, CCR2 - immunology / Receptors, Chemokine - deficiency / Receptors, Chemokine - genetics / Receptors, Chemokine - immunology / Research Article / Sensory Organs