Oxidative damage-induced inflammation initiates age-related macular degeneration

Joe G. Hollyfield; Vera L. Bonilha; Mary E. Rayborn; Xiaoping Yang; Karen G. Shadrach; Liang Lu; Rafael L. Ufret; Robert G. Salomon; Victor L. Perez

doi:10.1038/nm1709

Oxidative damage-induced inflammation initiates age-related macular degeneration

Joe G. Hollyfield, Vera L. Bonilha, Mary E. Rayborn, Xiaoping Yang, Karen G. Shadrach, Liang Lu, Rafael L. Ufret, Robert G. Salomon, Victor L. Perez

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

609 Scopus citations

Abstract

Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.

Original language	English (US)
Pages (from-to)	194-198
Number of pages	5
Journal	Nature medicine
Volume	14
Issue number	2
DOIs	https://doi.org/10.1038/nm1709
State	Published - Feb 2008

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm1709

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@article{2dbf30c1808842e7a4f5e44e3524f28c,

title = "Oxidative damage-induced inflammation initiates age-related macular degeneration",

abstract = "Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.",

author = "Hollyfield, {Joe G.} and Bonilha, {Vera L.} and Rayborn, {Mary E.} and Xiaoping Yang and Shadrach, {Karen G.} and Liang Lu and Ufret, {Rafael L.} and Salomon, {Robert G.} and Perez, {Victor L.}",

note = "Funding Information: Supported by the State of Ohio Biomedical Research and Technology Transfer Program, a Research Center Grant from the Foundation Fighting Blindness, and a Challenge Grant from Research to Prevent Blindness. The project was also supported by grants R56EY10240, R01EY014240, R24EY015638 (J.G.H.), R21EY017153 (V.L.B.), R01GM21249 (R.G.S.) and K08EY014912 (V.L.P.) from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Eye Institute of the National Institutes of Health. We thank J.W. Crabb for valuable discussions, B. Anand-Apte for critical comments on the manuscript, N.S. Peachey for help with the statistical comparisons, R.L. Fairchild for providing the Rag-deficient mice, Y. Li for help with the histology, K. Sayanagi and T. Yakamoto for the fundus photography and A. Vasanji for developing the image-analysis algorithm used to define the areas of sub-RPE deposits.",

year = "2008",

month = feb,

doi = "10.1038/nm1709",

language = "English (US)",

volume = "14",

pages = "194--198",

journal = "Nature medicine",

issn = "1078-8956",

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number = "2",

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T1 - Oxidative damage-induced inflammation initiates age-related macular degeneration

AU - Hollyfield, Joe G.

AU - Bonilha, Vera L.

AU - Rayborn, Mary E.

AU - Yang, Xiaoping

AU - Shadrach, Karen G.

AU - Lu, Liang

AU - Ufret, Rafael L.

AU - Salomon, Robert G.

AU - Perez, Victor L.

N1 - Funding Information: Supported by the State of Ohio Biomedical Research and Technology Transfer Program, a Research Center Grant from the Foundation Fighting Blindness, and a Challenge Grant from Research to Prevent Blindness. The project was also supported by grants R56EY10240, R01EY014240, R24EY015638 (J.G.H.), R21EY017153 (V.L.B.), R01GM21249 (R.G.S.) and K08EY014912 (V.L.P.) from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Eye Institute of the National Institutes of Health. We thank J.W. Crabb for valuable discussions, B. Anand-Apte for critical comments on the manuscript, N.S. Peachey for help with the statistical comparisons, R.L. Fairchild for providing the Rag-deficient mice, Y. Li for help with the histology, K. Sayanagi and T. Yakamoto for the fundus photography and A. Vasanji for developing the image-analysis algorithm used to define the areas of sub-RPE deposits.

PY - 2008/2

Y1 - 2008/2

N2 - Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.

AB - Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.

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JO - Nature medicine

JF - Nature medicine

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Oxidative damage-induced inflammation initiates age-related macular degeneration

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