TY - JOUR
T1 - How does the macula protect itself from oxidative stress?
AU - Handa, James T.
N1 - Funding Information:
This work was supported by NIH EY14005 , EY019904 , Edward N. and Della L. Thome Memorial Foundation Awards Program in AMD Research, Beckmann Award in Age-related Macular Degeneration, Senior Scientific Investigator Award from Research to Prevent Blindness, an unrestricted grant from Research to Prevent Blindness. Dr. Handa’s lab has also received generous gifts from the Merlau family. Dr. Handa is the Robert Bond Welch Professor. I thank Katayoon Ebrahimi, MD, for supplying the photomicrographs.
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
KW - Age-related macular degeneration
KW - Innate immune response
KW - Nrf2
KW - Oxidation specific epitope
KW - Oxidative stress
KW - Retinal pigment epithelium
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U2 - 10.1016/j.mam.2012.03.006
DO - 10.1016/j.mam.2012.03.006
M3 - Review article
C2 - 22503691
AN - SCOPUS:84863722159
SN - 0098-2997
VL - 33
SP - 418
EP - 435
JO - Molecular Aspects of Medicine
JF - Molecular Aspects of Medicine
IS - 4
ER -