Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age‐related macular degeneration

• Published in: EMBO molecular medicine Vol. 7; no. 2; pp. 211 - 226
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2015; EMBO Press; Wiley Open Access; BlackWell Publishing Ltd; Springer Nature
• Subjects: Age; age‐related macular degeneration; Alzheimer's disease; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - immunology; CD14 antigen; Cell Survival; Cholesterol; Choroidal Neovascularization; CX3C Chemokine Receptor 1; CX3CR1 protein; EMBO19; EMBO27; Epithelium; Experiments; Fas Ligand Protein - immunology; FasL protein; Human health and pathology; Humans; Inflammation; Innate immunity; interleukin 6; Interleukin-6 - genetics; Interleukin-6 - immunology; Leukocytes (mononuclear); Life Sciences; Lipids; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - immunology; Macular Degeneration - physiopathology; Male; Mice; Mice, Knockout; mononuclear phagocyte; neuroinflammation; Neurons and Cognition; Phagocytes; Phagocytes - cytology; Phagocytes - immunology; Photoreceptors; Receptor density; Receptors, Chemokine - genetics; Receptors, Chemokine - immunology; Research Article; Retina; Retinal degeneration; Retinal pigment epithelium; Retinal Pigment Epithelium - immunology; Sensory Organs; TLR2 protein; Toll-like receptors; Transgenic animals; Vascularization; apolipoprotein E; interleukin 6; mononuclear phagocyte; age‐related macular degeneration; neuroinflammation; neuroinflammation Subject Categories Immunology; Neuroscience; age-related macular degeneration
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201404524

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. Synopsis In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation. Pathogenic subretinal mononuclear phagocytes, observed in age‐related macular degeneration in human donor tissue and in the Cx3cr1 −/− mouse model of subretinal inflammation, express high levels of APOE. High levels of APOE activate the TLR2‐CD14‐dependent innate immunity receptor cluster and induce IL‐6 in mononuclear phagocytes. IL‐6 inhibits FASL expression in the retinal pigment epithelium and increases subretinal mononuclear phagocyte survival. ApoE deletion and pharmacological IL‐6 inhibition prevents pathogenic age‐ and stress‐induced subretinal MP accumulation in Cx3cr1 −/− mice. Graphical Abstract In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation.