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CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair
Open accessAbstract
Monocytes/macrophages are critical in orchestrating the tissue-repair response. However, the mechanisms that govern macrophage regenerative activities during the sequential phases of repair are largely unknown. In the present study, we examined the dynamics and functions of diverse monocyte/macrophage phenotypes during the sequential stages of skin repair. By combining the analysis of a new CCR2-eGFP reporter mouse model with conditional mouse mutants defective in myeloid cell-restricted CCR2 signaling or VEGF-A synthesis, we show herein that among the large number of inflammatory CCR2(+)Ly6C(+) macrophages that dominate the early stage of repair, only a small fraction strongly expresses VEGF-A that has nonredundant functions for the induction of vascular sprouts. The switch of macrophage-derived VEGF-A during the early stage of tissue growth toward epidermal-derived VEGF-A during the late stage of tissue maturation was critical to achieving physiologic tissue vascularization and healing progression. The results of the present study provide new mechanistic insights into CCR2-mediated recruitment of blood monocyte subsets into damaged tissue, the dynamics and functional consequences of macrophage plasticity during the sequential repair phases, and the complementary role of macrophage-derived VEGF-A in coordinating effective tissue growth and vascularization in the context of tissue-resident wound cells. Our findings may be relevant for novel monocyte-based therapies to promote tissue vascularization.
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“Recent studies have shown that Mp phenotypes change over the different phases of tissue repair and that the sequential appearance of these phenotypes may be required for efficient repair (11,14,29,49,50).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [11]
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“[74] demonstrated the importance of macrophage-derived factors in angiogenesis, where myeloid-specific deletion of VEGF-A reduced capillary formation in murine wounds.”
BackgroundMicroglial and macrophage polarization—new prospects for brain repair
Hu, X., Leak, R. K., Shi, Y., Suenaga, J., Gao, Y., Zheng, P., & Chen, J. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.207 · Cited by 1,366
Metadata
- Authors
- Willenborg, S., Lucas, T., van Loo, G., Knipper, J. A., Krieg, T., Haase, I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N., Pasparakis, M., & Eming, S. A.
- Affiliations
- University of Cologne (DE)
- Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium;
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON;
- Genentech (US)
- Corresponding author
- Willenborg, Sebastian
- Lucas, Tina
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-07-19
- Volume
- 120
- Issue
- 3
- Pages
- 613-625
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2065145765
- Cited by
- 534
- References
- 40
- Citations by year
- 2026: 29 · 2025: 43 · 2024: 38 · 2023: 55 · 2022: 46 · 2021: 40 · 2020: 40 · 2019: 34 · 2018: 38 · 2017: 43 · 2016: 32 · 2015: 29 · 2014: 37 · 2013: 24 · 2012: 5
- FWCI
- 32.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- European Commission (2007–2013, 214402)
- Deutsche Forschungsgemeinschaft
- Universiteit Gent
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- CCR2, macrophage plasticity, VEGF-A, angiogenesis, skin wound healing, tissue repair, monocyte recruitment, vascular sprouting, tissue vascularization
- MeSH terms
- Animals, Cells, Cultured, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Monocytes, Regeneration, Skin, Wound Healing, Signal Transduction, Macrophages, Peritoneal, Neovascularization, Physiologic, Gene Expression Profiling, Myeloid Cells, Vascular Endothelial Growth Factor A, Green Fluorescent Proteins, Mice, Receptors, CCR2
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