How does the macula protect itself from oxidative stress?

Research output: Contribution to journalReview articlepeer-review

Abstract

Oxidative stress has been hypothesized to contribute to the development of age-related macular degeneration (AMD), the most common cause of blindness in the United States. At present, there is no treatment for early disease. Reactive oxygen species (ROS) play a physiological role in the retinal pigment epithelium (RPE), a key cell type in this disease, but with excessive ROS, oxidative damage or excessive innate immune system activation can result. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2. Impaired Nrf2 signaling can lead to oxidative damage or activate the innate immune response, both of which can lead to RPE apoptosis, a defining change in AMD. Several mouse models simulating environmental stressors or targeting specific antioxidant enzymes such as superoxide dismutase or Nrf2, have simulated some of the features of AMD. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the innate immune system through pattern recognition receptors (PRRs). The macula accumulates a number of OSEs including carboxyethylpyrrole, malondialdehyde, 4-hydroxynonenal, and advanced glycation endproducts, as well as their respective neutralizing PRRs. Excessive accumulation of OSEs results in pathologic immune activation. For example, mice immunized with the carboxyethylpyrrole develop cardinal features of AMD. Regulating ROS in the RPE by modulating antioxidant systems or neutralizing OSEs through an appropriate innate immune response are potential modalities to treat or prevent early AMD.

Original languageEnglish (US)
Pages (from-to)418-435
Number of pages18
JournalMolecular Aspects of Medicine
Volume33
Issue number4
DOIs
StatePublished - Aug 2012

Keywords

  • Age-related macular degeneration
  • Innate immune response
  • Nrf2
  • Oxidation specific epitope
  • Oxidative stress
  • Retinal pigment epithelium

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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