Abstract
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.
Highlights
Age-related macular degeneration (AMD) is the leading cause of central irreversible blindness in people age 55 and older [1,2]
Twenty-seven AMD and four normal retinas were assayed in the periphery, but IL17A was below the detectable threshold for the Quantitative Reverse-transcriptase PCR (qRT-PCR) assay in all specimens
Using a combination of cell and animal studies, we found that IL17 signaling is damaging to cultured retinal pigment epithelium (RPE) and to the retina in a mouse model
Summary
Age-related macular degeneration (AMD) is the leading cause of central irreversible blindness in people age 55 and older [1,2]. The disease is characterized earliest by the appearance of extracellular material (drusen) in macular Bruch’s membrane and external to the retinal pigment epithelium (RPE). Many patients develop one of two phenotypes: geographic atrophy (GA or ‘‘dry AMD’’) characterized by atrophy of RPE and photoreceptors, or neovascular AMD (nAMD or ‘‘wet AMD’’) characterized by choroidal neovascularization (CNV). AMD risk factors include aging, smoking, and genetics, a common polymorphism in complement factor H. RPE damage is an inciting event believed to be the primary pathological insult leading to photoreceptor atrophy [3].
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