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.
authors.affiliation: Department of Dermatology, University of Cologne, Kerpenerstrasse 62, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Willenborg
authors.forename: Tina
authors.initials: T
authors.lastname: Lucas
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Knipper
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000276:immunology*; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012038:Regeneration / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000293:injuries; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology*
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D042461:Vascular Endothelial Growth Factor A; C485184:enhanced green fluorescent protein; C467480:vascular endothelial growth factor A, mouse; D049452:Green Fluorescent Proteins