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

Daniel Ardeljan; Yujuan Wang; Stanley Park; Defen Shen; Xi Kathy Chu; Cheng Rong Yu; Mones Abu-Asab; Jingsheng Tuo; Charles G. Eberhart; Timothy W. Olsen; Robert F. Mullins; Gary White; Sam Wadsworth; Abraham Scaria; Chi Chao Chan

doi:10.1371/journal.pone.0095900

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

Daniel Ardeljan, Yujuan Wang, Stanley Park, Defen Shen, Xi Kathy Chu, Cheng Rong Yu, Mones Abu-Asab, Jingsheng Tuo, Charles G. Eberhart, Timothy W. Olsen, Robert F. Mullins, Gary White, Sam Wadsworth, Abraham Scaria, Chi Chao Chan

Ophthalmology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Article number	e95900
Journal	PloS one
Volume	9
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0095900
State	Published - Apr 29 2014

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Ardeljan, D., Wang, Y., Park, S., Shen, D., Chu, X. K., Yu, C. R., Abu-Asab, M., Tuo, J., Eberhart, C. G., Olsen, T. W., Mullins, R. F., White, G., Wadsworth, S., Scaria, A., & Chan, C. C. (2014). 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. PloS one, 9(4), Article e95900. https://doi.org/10.1371/journal.pone.0095900

Ardeljan, D, Wang, Y, Park, S, Shen, D, Chu, XK, Yu, CR, Abu-Asab, M, Tuo, J, Eberhart, CG, Olsen, TW, Mullins, RF, White, G, Wadsworth, S, Scaria, A & Chan, CC 2014, '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', PloS one, vol. 9, no. 4, e95900. https://doi.org/10.1371/journal.pone.0095900

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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.",

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AU - Olsen, Timothy W.

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AU - Wadsworth, Sam

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AU - Chan, Chi Chao

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AB - 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.

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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

Abstract

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