Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age‐related macular degeneration. Issue 2 (20th January 2015)

• Record Type: Journal Article
• Authors: Levy, Olivier; Calippe, Bertrand; Lavalette, Sophie; Hu, Shulong J; Raoul, William; Dominguez, Elisa; Housset, Michael; Paques, Michel; Sahel, José‐Alain; Bemelmans, Alexis‐Pierre; Combadiere, Christophe; Guillonneau, Xavier; Sennlaub, Florian
• Is Part Of: EMBO molecular medicine. Volume 7:Issue 2(2015:Feb.)
• Page Start: 211
• Page End: 226
• Publication Date: 2015-01-20
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404524
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201404524-abs-0001"> <title>Abstract</title> <p>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 <italic>Cx3cr1</italic><sup>−/−</sup> mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization similarly express high levels of APOE. <italic>ApoE</italic> deletion in <italic>Cx3cr1</italic><sup>−/−</sup> 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 <italic>Cx3cr1</italic><sup>−/−</sup> 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.</p> </abstract>