How does the macula protect itself from oxidative stress? - PubMed (original) (raw)

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How does the macula protect itself from oxidative stress?

James T Handa. Mol Aspects Med. 2012 Aug.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

a) Color fundus photograph of a normal left macula. ON, optic nerve. b) Photomicrograph of a normal macula. Note the multilayer ganglion cell layer (GCL). NFL, nerve fiber layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PR, photoreceptor layer; RPE, retinal pigment epithelium; BrM, Bruch’s membrane. Bar=50µm.

Figure 1

Figure 1

a) Color fundus photograph of a normal left macula. ON, optic nerve. b) Photomicrograph of a normal macula. Note the multilayer ganglion cell layer (GCL). NFL, nerve fiber layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PR, photoreceptor layer; RPE, retinal pigment epithelium; BrM, Bruch’s membrane. Bar=50µm.

Figure 2

Figure 2

Fundus photograph of a left macula with many large drusen. The area of greatest involvement is outlined by the arrows.

Figure 3

Figure 3

Schematic diagram of degenerative changes to the RPE and Bruch’s membrane during the progression of AMD. A) Normal cuboidal morphology of the RPE. Bruch’s membrane (BrM) is normal thickness. CC, choriocapillaris. B) Flattening of the RPE with early basal laminar deposit (BlamD). C) Further flattening of the RPE with development of more advanced basal laminar deposits and development of basal linear deposits (BlinD). Heterogeneous debris (Yellow deposits) accumulates in both BlamD and BlinD. D) Atrophic RPE overlying large druse.

Figure 4

Figure 4

Photomicrograph of drusen, highlighted by the arrows. Bar=50µm.

Figure 5

Figure 5

Schematic diagram of Nrf2 signaling. ARE, antioxidant response element; Cul3, Cullin3-dependent E3 ubiquitin ligase complex; Keap1, Kelch-like ECH-associated protein 1; Nrf2, Nuclear factor erythroid-2 related factor 2; Maf, musculoaponeurotic fibrosarcoma protein; ROS, reactive oxygen species.

Figure 6

Figure 6

Proposed scheme of oxidative stress and its antioxidant systems including the Nrf2 signaling system and the innate immune system’s activation by oxidation specific epitopes (OSEs). CS, cigarette smoking; PRR, pattern recognition receptor; ROS, reactive oxygen species; UV, photo-oxidative stress.

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