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. 2014 Apr 29;9(4):e95900. doi: 10.1371/journal.pone.0095900. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / antagonists & inhibitors*
  • Dependovirus / genetics
  • Genetic Vectors
  • Humans
  • Interleukin-17 / toxicity*
  • Macular Degeneration / genetics
  • Macular Degeneration / prevention & control*
  • Receptors, Interleukin-17 / genetics*
  • Retina / drug effects*
  • Transfection*

Substances

  • Cytokines
  • Interleukin-17
  • Receptors, Interleukin-17

Grants and funding

The National Eye Institute Intramural Research Program & Genzyme funded the work. The funder Genzyme provided support in the form of salaries for authors GW, SW, and AS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.