Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.
Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America; School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Daniel
D
Ardeljan
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Yujuan
Y
Wang
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
Stanley
S
Park
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Defen
D
Shen
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Xi Kathy
XK
Chu
Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Cheng-Rong
CR
Yu
Histology Core, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Mones
M
Abu-Asab
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Jingsheng
J
Tuo
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Charles G
CG
Eberhart
Department of Ophthalmology, Emory University, Atlanta, Georgia, United States of America.
Timothy W
TW
Olsen
Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
Robert F
RF
Mullins
Genzyme Corporation, Framingham, Massachusetts, United States of America.
Gary
G
White
Genzyme Corporation, Framingham, Massachusetts, United States of America.
Sam
S
Wadsworth
Genzyme Corporation, Framingham, Massachusetts, United States of America.
Abraham
A
Scaria
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Chi-Chao
CC
Chan
D016207:Cytokines / Q000037:antagonists & inhibitors*; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D020381:Interleukin-17 / Q000633:toxicity*; D008268:Macular Degeneration / Q000235:genetics / Q000517:prevention & control*; D053722:Receptors, Interleukin-17 / Q000235:genetics*; D012160:Retina / Q000187:drug effects*; D014162:Transfection
D016207:Cytokines; D020381:Interleukin-17; D053722:Receptors, Interleukin-17