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

被引：110

作者：

Levy, Olivier ^{[1
,2
,3
]}

Calippe, Bertrand ^{[1
,2
,3
]}

Lavalette, Sophie ^{[1
,2
,3
]}

Hu, Shulong J. ^{[1
,2
,3
]}

Raoul, William ^{[1
,2
,3
]}

Dominguez, Elisa ^{[1
,2
,3
]}

Housset, Michael ^{[1
,2
,3
]}

Paques, Michel ^{[1
,2
,3
]}

Sahel, Jose-Alain ^{[1
,2
,3
]}

Bemelmans, Alexis-Pierre ^{[1
,2
,3
,4
,5
]}

Combadiere, Christophe ^{[6
,7
,8
]}

Guillonneau, Xavier ^{[1
,2
,3
]}

Sennlaub, Florian ^{[1
,2
,3
]}

机构：

[1] INSERM, Paris, France

[2] Univ Paris 06, Inst Vis, UMR S 968, Paris, France

[3] Ctr Hosp Natl Ophtalmol Quinze Vingts, INSERM DHOS CIC 503, Paris, France

[4] CEA, DSV, I2BM, Mol Imaging Res Ctr MIRCen, Fontenay Aux Roses, France

[5] CNRS, CEA URA 2210, Fontenay Aux Roses, France

[6] Univ Paris 06, Univ Sorbonne, CR7, Ctr Immunol & Malad Infect CIMI Paris, Paris, France

[7] INSERM, CIMI Paris, U1135, Paris, France

[8] CNRS, CIMI Paris, ERL 8255, Paris, France

来源：

EMBO MOLECULAR MEDICINE | 2015年 / 7卷 / 02期

关键词：

age-related macular degeneration; apolipoprotein E; interleukin; 6; mononuclear phagocyte; neuroinflammation; REVERSE CHOLESTEROL TRANSPORT; RETINAL DEGENERATION; HUMAN MONOCYTES; APOPROTEIN-E; MACROPHAGES; EXPRESSION; MICROGLIA; APOPTOSIS; APOE; ACTIVATION;

D O I：

10.15252/emmm.201404524

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：211 / 226

页数：16

共 69 条

[21] An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration [J].