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The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration.

Chen H, Liu B, Lukas TJ, Neufeld AH - PLoS ONE (2008)

Bottom Line: Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling.There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade.These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.

View Article: PubMed Central - PubMed

Affiliation: Forsythe Laboratory for the Investigation of the Aging Retina, Department of Ophthalmology, Northwestern University School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT

Background: Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD.

Methodology/principal findings: We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.

Conclusions/significance: These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.

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Changes in gene expression in RPE/choroid from old animals.(A) The transcriptional profiles of the normal RPE/choroid from young and old mice were analyzed by hierarchical clustering of 315 differentially expressed, age-regulated genes by Limma analysis. Standardized expression values of genes are displayed according to the color scale, in which red represents above average expression and green represents below average expression. Absolute fold changes of individual genes are shown in Table S1 online. (B) Relative changes in canonical pathways in RPE/choroid from old animals. The upper figure shows the –log (p value) of the first 10 canonical pathways which changed significantly in RPE/choroid from old animals. The horizontal line represents the threshold of p which is equivalent to p = 0.05. Bars above the line indicate p<0.05. The lower part of the figure shows the number of differentially expressed genes in each pathway. (C) The –log (p value) of the 9 canonical pathways which changed significantly in neural retina from old animals.
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pone-0002339-g001: Changes in gene expression in RPE/choroid from old animals.(A) The transcriptional profiles of the normal RPE/choroid from young and old mice were analyzed by hierarchical clustering of 315 differentially expressed, age-regulated genes by Limma analysis. Standardized expression values of genes are displayed according to the color scale, in which red represents above average expression and green represents below average expression. Absolute fold changes of individual genes are shown in Table S1 online. (B) Relative changes in canonical pathways in RPE/choroid from old animals. The upper figure shows the –log (p value) of the first 10 canonical pathways which changed significantly in RPE/choroid from old animals. The horizontal line represents the threshold of p which is equivalent to p = 0.05. Bars above the line indicate p<0.05. The lower part of the figure shows the number of differentially expressed genes in each pathway. (C) The –log (p value) of the 9 canonical pathways which changed significantly in neural retina from old animals.

Mentions: The microarray data from RPE/choroid have been deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE10965. By comparing RPE/choroid tissues from young and old animals, the analyses of our microarray data showed consistent results and distinctive transcriptional profiles. There were 315 differentially expressed genes from the analysis using Limma (Table S1), 300 from DNA-Chip Analyzer (Dchip) and 309 from Significance Analysis of Microarrays (SAM). 227 genes were in common for the three analytical methods. To identify the distinctive transcriptional profile, we performed hierarchical clustering to analyze the 315 differentially expressed genes from Limma analysis. A clustering map is shown in Figure 1 A, comparing the expression of 315 genes in the RPE/choroid from young and old animals and clearly demonstrating marked differences. Among the 315 genes, 33 genes were decreased and 282 genes were increased with age.


The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration.

Chen H, Liu B, Lukas TJ, Neufeld AH - PLoS ONE (2008)

Changes in gene expression in RPE/choroid from old animals.(A) The transcriptional profiles of the normal RPE/choroid from young and old mice were analyzed by hierarchical clustering of 315 differentially expressed, age-regulated genes by Limma analysis. Standardized expression values of genes are displayed according to the color scale, in which red represents above average expression and green represents below average expression. Absolute fold changes of individual genes are shown in Table S1 online. (B) Relative changes in canonical pathways in RPE/choroid from old animals. The upper figure shows the –log (p value) of the first 10 canonical pathways which changed significantly in RPE/choroid from old animals. The horizontal line represents the threshold of p which is equivalent to p = 0.05. Bars above the line indicate p<0.05. The lower part of the figure shows the number of differentially expressed genes in each pathway. (C) The –log (p value) of the 9 canonical pathways which changed significantly in neural retina from old animals.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2394659&req=5

pone-0002339-g001: Changes in gene expression in RPE/choroid from old animals.(A) The transcriptional profiles of the normal RPE/choroid from young and old mice were analyzed by hierarchical clustering of 315 differentially expressed, age-regulated genes by Limma analysis. Standardized expression values of genes are displayed according to the color scale, in which red represents above average expression and green represents below average expression. Absolute fold changes of individual genes are shown in Table S1 online. (B) Relative changes in canonical pathways in RPE/choroid from old animals. The upper figure shows the –log (p value) of the first 10 canonical pathways which changed significantly in RPE/choroid from old animals. The horizontal line represents the threshold of p which is equivalent to p = 0.05. Bars above the line indicate p<0.05. The lower part of the figure shows the number of differentially expressed genes in each pathway. (C) The –log (p value) of the 9 canonical pathways which changed significantly in neural retina from old animals.
Mentions: The microarray data from RPE/choroid have been deposited in NCBIs Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE10965. By comparing RPE/choroid tissues from young and old animals, the analyses of our microarray data showed consistent results and distinctive transcriptional profiles. There were 315 differentially expressed genes from the analysis using Limma (Table S1), 300 from DNA-Chip Analyzer (Dchip) and 309 from Significance Analysis of Microarrays (SAM). 227 genes were in common for the three analytical methods. To identify the distinctive transcriptional profile, we performed hierarchical clustering to analyze the 315 differentially expressed genes from Limma analysis. A clustering map is shown in Figure 1 A, comparing the expression of 315 genes in the RPE/choroid from young and old animals and clearly demonstrating marked differences. Among the 315 genes, 33 genes were decreased and 282 genes were increased with age.

Bottom Line: Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling.There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade.These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.

View Article: PubMed Central - PubMed

Affiliation: Forsythe Laboratory for the Investigation of the Aging Retina, Department of Ophthalmology, Northwestern University School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT

Background: Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD.

Methodology/principal findings: We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.

Conclusions/significance: These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.

Show MeSH
Related in: MedlinePlus