CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair

Sebastian Willenborg, Tina Lucas, Geert Van Loo, Johanna A. Knipper, Thomas Krieg, Ingo Haase, Bent Brachvogel, Matthias Hammerschmidt, Andras Nagy, Napoleone Ferrara, Manolis Pasparakis, Sabine A. Eming

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)613-625
Number of pages13
JournalBlood
Volume120
Issue number3
DOIs
Publication statusPublished - 19 Jul 2012
Externally publishedYes

Cite this

Willenborg, S., Lucas, T., Van Loo, G., Knipper, J. A., Krieg, T., Haase, I., ... Eming, S. A. (2012). CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, 120(3), 613-625. https://doi.org/10.1182/blood-2012-01-403386
Willenborg, Sebastian ; Lucas, Tina ; Van Loo, Geert ; Knipper, Johanna A. ; Krieg, Thomas ; Haase, Ingo ; Brachvogel, Bent ; Hammerschmidt, Matthias ; Nagy, Andras ; Ferrara, Napoleone ; Pasparakis, Manolis ; Eming, Sabine A. / CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. In: Blood. 2012 ; Vol. 120, No. 3. pp. 613-625.
@article{fec501a9f3894d54b21e58a1cd3c91f2,
title = "CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair",
abstract = "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.",
author = "Sebastian Willenborg and Tina Lucas and {Van Loo}, Geert and Knipper, {Johanna A.} and Thomas Krieg and Ingo Haase and Bent Brachvogel and Matthias Hammerschmidt and Andras Nagy and Napoleone Ferrara and Manolis Pasparakis and Eming, {Sabine A.}",
year = "2012",
month = "7",
day = "19",
doi = "10.1182/blood-2012-01-403386",
language = "English",
volume = "120",
pages = "613--625",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "3",

}

Willenborg, S, Lucas, T, Van Loo, G, Knipper, JA, Krieg, T, Haase, I, Brachvogel, B, Hammerschmidt, M, Nagy, A, Ferrara, N, Pasparakis, M & Eming, SA 2012, 'CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair' Blood, vol. 120, no. 3, pp. 613-625. https://doi.org/10.1182/blood-2012-01-403386

CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. / Willenborg, Sebastian; Lucas, Tina; Van Loo, Geert; Knipper, Johanna A.; Krieg, Thomas; Haase, Ingo; Brachvogel, Bent; Hammerschmidt, Matthias; Nagy, Andras; Ferrara, Napoleone; Pasparakis, Manolis; Eming, Sabine A.

In: Blood, Vol. 120, No. 3, 19.07.2012, p. 613-625.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair

AU - Willenborg, Sebastian

AU - Lucas, Tina

AU - Van Loo, Geert

AU - Knipper, Johanna A.

AU - Krieg, Thomas

AU - Haase, Ingo

AU - Brachvogel, Bent

AU - Hammerschmidt, Matthias

AU - Nagy, Andras

AU - Ferrara, Napoleone

AU - Pasparakis, Manolis

AU - Eming, Sabine A.

PY - 2012/7/19

Y1 - 2012/7/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84864126835&partnerID=8YFLogxK

U2 - 10.1182/blood-2012-01-403386

DO - 10.1182/blood-2012-01-403386

M3 - Article

VL - 120

SP - 613

EP - 625

JO - Blood

JF - Blood

SN - 0006-4971

IS - 3

ER -

Willenborg S, Lucas T, Van Loo G, Knipper JA, Krieg T, Haase I et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012 Jul 19;120(3):613-625. https://doi.org/10.1182/blood-2012-01-403386