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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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Related in: MedlinePlus

Pathway diagram showing the molecules involved in leukocyte extravasation signaling and their interaction.Color nodes: genes that changed significantly in RPE/choroid from old animals with a fold change >2. Red: upregulation; green: downregulation. The diagram was modified from Ingenuity Pathway Analysis (Ingenuity® Systems).
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pone-0002339-g003: Pathway diagram showing the molecules involved in leukocyte extravasation signaling and their interaction.Color nodes: genes that changed significantly in RPE/choroid from old animals with a fold change >2. Red: upregulation; green: downregulation. The diagram was modified from Ingenuity Pathway Analysis (Ingenuity® Systems).

Mentions: The pathway with changes of the highest significance was leukocyte extravasation signaling (p<10−16). There were 24 genes in this pathway that significantly changed in the aged RPE/choroid by Limma analysis and almost all showed significant changes by Dchip and SAM analyses (Table 1; Fig. 1 B and 2 A). Expression of 23 genes was increased, suggesting high leukocyte extravasation activity in the RPE/choroid of old animals. The upregulated genes are involved in leukocyte rolling and docking on endothelial surfaces of capillaries and leukocyte transmigration through capillary endothelial layers (Fig. 3). Several membrane receptors that are crucial for interaction between leukocytes and endothelial cells and for enhancing leukocytes recruitment [22]–[25] showed significantly increased expression in the RPE/choroid of old animals, including: ITGAM (αM-integrin), ITGB2 (β2-integrin), ITGAL (αL-integrin) and ICAM1 (intercellular adhesion molecule 1). In addition, expression of matrix metallproteases, that are important effectors of inflammatory processes and also essential for leukocyte extravasation and migration [26], [27], was also significantly increased, notably: MMP3 (matrix metalloprotease 3) and MMP13 (matrix metalloprotease 13).


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)

Pathway diagram showing the molecules involved in leukocyte extravasation signaling and their interaction.Color nodes: genes that changed significantly in RPE/choroid from old animals with a fold change >2. Red: upregulation; green: downregulation. The diagram was modified from Ingenuity Pathway Analysis (Ingenuity® Systems).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394659&req=5

pone-0002339-g003: Pathway diagram showing the molecules involved in leukocyte extravasation signaling and their interaction.Color nodes: genes that changed significantly in RPE/choroid from old animals with a fold change >2. Red: upregulation; green: downregulation. The diagram was modified from Ingenuity Pathway Analysis (Ingenuity® Systems).
Mentions: The pathway with changes of the highest significance was leukocyte extravasation signaling (p<10−16). There were 24 genes in this pathway that significantly changed in the aged RPE/choroid by Limma analysis and almost all showed significant changes by Dchip and SAM analyses (Table 1; Fig. 1 B and 2 A). Expression of 23 genes was increased, suggesting high leukocyte extravasation activity in the RPE/choroid of old animals. The upregulated genes are involved in leukocyte rolling and docking on endothelial surfaces of capillaries and leukocyte transmigration through capillary endothelial layers (Fig. 3). Several membrane receptors that are crucial for interaction between leukocytes and endothelial cells and for enhancing leukocytes recruitment [22]–[25] showed significantly increased expression in the RPE/choroid of old animals, including: ITGAM (αM-integrin), ITGB2 (β2-integrin), ITGAL (αL-integrin) and ICAM1 (intercellular adhesion molecule 1). In addition, expression of matrix metallproteases, that are important effectors of inflammatory processes and also essential for leukocyte extravasation and migration [26], [27], was also significantly increased, notably: MMP3 (matrix metalloprotease 3) and MMP13 (matrix metalloprotease 13).

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