Cargando…

VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization

Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their p...

Descripción completa

Detalles Bibliográficos
Autores principales: Krause, Torsten A., Alex, Anne F., Engel, Daniel R., Kurts, Christian, Eter, Nicole
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979804/
https://www.ncbi.nlm.nih.gov/pubmed/24714223
http://dx.doi.org/10.1371/journal.pone.0094313
_version_ 1782310769049731072
author Krause, Torsten A.
Alex, Anne F.
Engel, Daniel R.
Kurts, Christian
Eter, Nicole
author_facet Krause, Torsten A.
Alex, Anne F.
Engel, Daniel R.
Kurts, Christian
Eter, Nicole
author_sort Krause, Torsten A.
collection PubMed
description Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their precursors, for example monocytes, can be recruited to sites of inflammation by the chemokine receptor CCR2, and this has been proposed to be important in AMD. To investigate the role of macrophages and CCR2 in AMD, we studied intracellular VEGF content in a laser-induced murine model of choroidal neovascularisation. To this end, we established a technique to quantify the VEGF content in cell subsets from the laser-treated retina and choroid separately. 3 days after laser, macrophage numbers and their VEGF content were substantially elevated in the choroid. Macrophage accumulation was CCR2-dependent, indicating recruitment from the circulation. In the retina, microglia cells were the main VEGF(+) phagocyte type. A greater proportion of microglia cells contained VEGF after laser, and this was CCR2-independent. On day 6, VEGF-expressing macrophage numbers had already declined, whereas numbers of VEGF(+) microglia cells remained increased. Other sources of VEGF detectable by flow cytometry included in dendritic cells and endothelial cells in both retina and choroid, and Müller cells/astrocytes in the retina. However, their VEGF content was not increased after laser. When we analyzed flatmounts of laser-treated eyes, CCR2-deficient mice showed reduced neovascular areas after 2 weeks, but this difference was not evident 3 weeks after laser. In summary, CCR2-dependent influx of macrophages causes a transient VEGF increase in the choroid. However, macrophages augmented choroidal neovascularization only initially, presumably because VEGF production by CCR2-independent eye cells prevailed at later time points. These findings identify macrophages as a relevant source of VEGF in laser-induced choroidal neovascularization but suggest that the therapeutic efficacy of CCR2-inhibition might be limited.
format Online
Article
Text
id pubmed-3979804
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39798042014-04-11 VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization Krause, Torsten A. Alex, Anne F. Engel, Daniel R. Kurts, Christian Eter, Nicole PLoS One Research Article Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their precursors, for example monocytes, can be recruited to sites of inflammation by the chemokine receptor CCR2, and this has been proposed to be important in AMD. To investigate the role of macrophages and CCR2 in AMD, we studied intracellular VEGF content in a laser-induced murine model of choroidal neovascularisation. To this end, we established a technique to quantify the VEGF content in cell subsets from the laser-treated retina and choroid separately. 3 days after laser, macrophage numbers and their VEGF content were substantially elevated in the choroid. Macrophage accumulation was CCR2-dependent, indicating recruitment from the circulation. In the retina, microglia cells were the main VEGF(+) phagocyte type. A greater proportion of microglia cells contained VEGF after laser, and this was CCR2-independent. On day 6, VEGF-expressing macrophage numbers had already declined, whereas numbers of VEGF(+) microglia cells remained increased. Other sources of VEGF detectable by flow cytometry included in dendritic cells and endothelial cells in both retina and choroid, and Müller cells/astrocytes in the retina. However, their VEGF content was not increased after laser. When we analyzed flatmounts of laser-treated eyes, CCR2-deficient mice showed reduced neovascular areas after 2 weeks, but this difference was not evident 3 weeks after laser. In summary, CCR2-dependent influx of macrophages causes a transient VEGF increase in the choroid. However, macrophages augmented choroidal neovascularization only initially, presumably because VEGF production by CCR2-independent eye cells prevailed at later time points. These findings identify macrophages as a relevant source of VEGF in laser-induced choroidal neovascularization but suggest that the therapeutic efficacy of CCR2-inhibition might be limited. Public Library of Science 2014-04-08 /pmc/articles/PMC3979804/ /pubmed/24714223 http://dx.doi.org/10.1371/journal.pone.0094313 Text en © 2014 Krause et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Krause, Torsten A.
Alex, Anne F.
Engel, Daniel R.
Kurts, Christian
Eter, Nicole
VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title_full VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title_fullStr VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title_full_unstemmed VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title_short VEGF-Production by CCR2-Dependent Macrophages Contributes to Laser-Induced Choroidal Neovascularization
title_sort vegf-production by ccr2-dependent macrophages contributes to laser-induced choroidal neovascularization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979804/
https://www.ncbi.nlm.nih.gov/pubmed/24714223
http://dx.doi.org/10.1371/journal.pone.0094313
work_keys_str_mv AT krausetorstena vegfproductionbyccr2dependentmacrophagescontributestolaserinducedchoroidalneovascularization
AT alexannef vegfproductionbyccr2dependentmacrophagescontributestolaserinducedchoroidalneovascularization
AT engeldanielr vegfproductionbyccr2dependentmacrophagescontributestolaserinducedchoroidalneovascularization
AT kurtschristian vegfproductionbyccr2dependentmacrophagescontributestolaserinducedchoroidalneovascularization
AT eternicole vegfproductionbyccr2dependentmacrophagescontributestolaserinducedchoroidalneovascularization