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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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Citations
Cites
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
Myeloid-derived-suppressor cells as regulators of the immune system
Gabrilovich, D. I., & Nagaraj, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2506 · Cited by 6,753
Gurtner, G. C., Werner, S., Barrandon, Y., & Longaker, M. T. (2008) · Nature · doi:10.1038/nature07039 · Cited by 6,542
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
Macrophage Diversity Enhances Tumor Progression and Metastasis
Qian, B., & Pollard, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.03.014 · Cited by 5,349
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190
Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties
Geissmann, F., Jung, S., & Littman, D. R. (2003) · Immunity · doi:10.1016/s1074-7613(03)00174-2 · Cited by 3,504
VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia
Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., Jeltsch, M., Mitchell, C., Alitalo, K., Shima, D., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200302047 · Cited by 2,894
CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis
Qian, B.-Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., Kaiser, E. A., Snyder, L. A., & Pollard, J. W. (2011) · Nature · doi:10.1038/nature10138 · Cited by 2,874
Inflammation in Wound Repair: Molecular and Cellular Mechanisms
Eming, S. A., Krieg, T., & Davidson, J. M. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700701 · Cited by 2,429
Self-citation
Cited by
Sorted by citations
Macrophages in Tissue Repair, Regeneration, and Fibrosis
Wynn, T. A., & Vannella, K. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.015 · Cited by 4,481
Wound Healing: A Cellular Perspective
Rodrigues, M., Kosaric, N., Bonham, C. A., & Gurtner, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00067.2017 · Cited by 3,211
From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation
Italiani, P., & Boraschi, D. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00514 · Cited by 2,067
“A reduction was also observed in skin wounds on the first day from injury, when Ly6C cells are those principally involved in the early repair phases, but not during the late stage of tissue repair, when Ly6C cells are dominant (151).”
BackgroundWound healing: cellular mechanisms and pathological outcomes
Wilkinson, H. N., & Hardman, M. J. (2020) · Open Biology · doi:10.1098/rsob.200223 · Cited by 1,975
“[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
Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair
Johnson, K. E., & Wilgus, T. A. (2014) · Advances in Wound Care · doi:10.1089/wound.2013.0517 · Cited by 1,169
Blood-brain barrier dysfunction and recovery after ischemic stroke
Jiang, X., Andjelkovic, A. V., Zhu, L., Yang, T., Bennett, M. V. L., Chen, J., Keep, R. F., & Shi, Y. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.10.001 · Cited by 967
Design of biodegradable, implantable devices towards clinical translation
Li, C., Guo, C., Fitzpatrick, V., Ibrahim, A. G. A., Zwierstra, M. J., Hanna, P. C., Lechtig, A., Nazarian, A., Lin, S. J., & Kaplan, D. L. (2019) · Nature Reviews Materials · doi:10.1038/s41578-019-0150-z · Cited by 828
Microglia in the TBI brain: The good, the bad, and the dysregulated
Loane, D. J., & Kumar, A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.08.018 · Cited by 850
“…angiogenesis 321D.J. Loane, A. Kumar / Experimental Neurology 275 (2016) 316–327 and vascular repair is currently unknown, M2-polarized macrophages play a critical role in vascular repair and wound healing (Jetten et al., 2014; Medina et al., 2011; Willenborg et al., 2012; Zajac et al., 2013).”
BackgroundPromoting tissue regeneration by modulating the immune system
Julier, Z., Park, A. J., Briquez, P. S., & Martino, M. M. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.01.056 · Cited by 766
Immunoregulation in Diabetic Wound Repair with a Photoenhanced Glycyrrhizic Acid Hydrogel Scaffold
Qian, Y., Zheng, Y., Jin, J., Wu, X., Xu, K., Dai, M., Niu, Q., Zheng, H., He, X., & Shen, J. (2022) · Advanced Materials · doi:10.1002/adma.202200521 · Cited by 769
Macrophage polarization in pathology
Sica, A., Erreni, M., Allavena, P., & Porta, C. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1995-y · Cited by 673
“In the remodeling phase, macrophages undergo phenotypic changes, increasing the expression of CD206 and CD163, producing TGF-b and several matrix proteases, and decreasing the expression of VEGF, arginase I, and insulin-like growth factor [37, 45].”
BackgroundSkin Acute Wound Healing: A Comprehensive Review
Cañedo‐Dorantes, L., & Cañedo-Ayala, M. (2019) · International Journal of Inflammation · doi:10.1155/2019/3706315 · Cited by 742
“Hypoxic conditions stimulate the synthesis of hypoxia inducible factor-1 (HIF1) in macrophages [133, 134], fibroblasts [41, 135], vascular endothelial cells [136], and keratinocytes [137].”
The Dynamics of the Skin’s Immune System
Nguyen, A. V., & Soulika, A. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081811 · Cited by 759
“Macrophage subsets exert multiple functions such as clearance of invading pathogens, secretion of growth factors that can stimulate revascularization and tissue repair, and expression of metalloproteases that are involved in restoration of the tissue architecture [368,381,382].”
BackgroundMechanisms of Organ Injury and Repair by Macrophages
Vannella, K. M., & Wynn, T. A. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034356 · Cited by 656
Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing
Boniakowski, A. E., Kimball, A., Jacobs, B. N., Kunkel, S. L., & Gallagher, K. A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700223 · Cited by 564
“Indeed, recent publications have corroborated these findings demonstrating that Ly6C and Ly6C MoMFs are recruited to myocardium after myocardial infarction, liver parenchyma after hepatocellular injury, and skin after wounding to fulfill roles similar to both proinflammatory and anti-inflammatory MoMFs, respectively (…”
BackgroundHost STING-dependent MDSC mobilization drives extrinsic radiation resistance
Liang, H. L., Deng, L., Hou, Y., Meng, X., Huang, X., Rao, E., Zheng, W., Mauceri, H. J., Mack, M., Xu, M. M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01566-5 · Cited by 502
Greaves, N. S., Ashcroft, K. J., Baguneid, M. S., & Bayat, A. (2013) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2013.07.008 · Cited by 493
“of Ly6C inflammatory circulating blood monocytes into cutaneous wounds that give rise to a highly proangiogenic VEGF-expressing macrophage subset resulting in induction of vascular sprouts during early phases of healing [91].”
BackgroundInfluentialTissue-specific contribution of macrophages to wound healing
Minutti, C. M., Knipper, J. A., Allen, J. E., & Zaiss, D. M. W. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.006 · Cited by 488
Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke
Hu, X., Silva, T. M. D., Chen, J., & Faraci, F. M. (2017) · Circulation Research · doi:10.1161/circresaha.116.308427 · Cited by 456
The role of the extracellular matrix components in cutaneous wound healing
Olczyk, P., Mencner, Ł., & Komosinska-Vassev, K. (2014) · BioMed Research International · doi:10.1155/2014/747584 · Cited by 387
“The mentioned mediators do not only control the inflammatory process but alsomodulate the epithelialization, collagen accumulation, and angiogenesis [35, 37, 39, 60].”
BackgroundFerrante, C. J., Pinhal-Enfield, G., Elson, G., Cronstein, B. N., Hasko, G., Outram, S., & Leibovich, S. J. (2013) · Inflammation · doi:10.1007/s10753-013-9621-3 · Cited by 375
“In particular, macrophages are central to the development and stabilization of new blood vessels in the injured area [37].”
Martin, K. E., & Garcı́a, A. J. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.03.038 · Cited by 384
Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis
Corliss, B. A., Azimi, M. S., Munson, J. M., Peirce, S. M., & Murfee, W. L. (2016) · Microcirculation · doi:10.1111/micc.12259 · Cited by 356
“In this study, VEGF-A-expressing macrophages that were recruited to the wound site exhibited characteristics of M1 and M2 macrophage subsets, including expression of the proinflammatory mediators IL-6 and iNOS, as well as Tie-2, which has been shown to be expressed by tumor-associated, M2-like macrophages [298].”
BackgroundPhenotypic Transitions of Macrophages Orchestrate Tissue Repair
Novak, M. L., & Koh, T. J. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.06.034 · Cited by 370
“Monocytes/macrophages of the late inflammatory and early proliferative phases express abundant proinflammatory cytokines, arginase, and VEGF, which can promote proliferation of numerous cell types involved in healing.(6,22,25,45) As the inflammatory phase declines and the proliferative phase progresses, macrophages in…”
BackgroundInfluentialEpigenetic regulation of macrophages: from homeostasis maintenance to host defense
Chen, S., Yang, J., Wei, Y., & Wei, X. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0315-0 · Cited by 331
“During the late stage of repair, macrophages provide an M2 gene-expression profile predominantly, resulting in an increase in the number of M2 (healing-promoting) macrophages and the release of growth factors such as TGF-β, IL-10 and IGF.(131) Delayed wound healing is a serious diabetes-related complication that often…”
BackgroundInfluentialMirza, R. E., Fang, M. M., Weinheimer-Haus, E. M., Ennis, W. J., & Koh, T. J. (2014) · Diabetes · doi:10.2337/db13-0927 · Cited by 319
Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair
Knipper, J. A., Willenborg, S., Brinckmann, J., Bloch, W., Maaß, T., Wagener, R., Krieg, T. M., Sutherland, T. E., Munitz, A., Rothenberg, M. E., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.09.005 · Cited by 326
Willenborg, S., Sanin, D. E., Jais, A., Ding, X., Ulas, T., Nüchel, J., Popović, M., MacVicar, T., Langer, T., Schultze, J. L., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.004 · Cited by 310
Macrophage-based therapeutic strategies in regenerative medicine
Spiller, K. L., & Koh, T. J. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.010 · Cited by 310
Dermal Adipocyte Lipolysis and Myofibroblast Conversion Are Required for Efficient Skin Repair
Shook, B. A., Wasko, R. R., Mano, O., Rutenberg-Schoenberg, M., Rudolph, M. C., Zirak, B., Rivera-Gonzalez, G. C., López‐Giráldez, F., Zarini, S., Rezza, A., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.03.013 · Cited by 295
“Specifically, wounds of mice lacking dermal adipocytes had fewer inflammatory Ly6CHi macrophages that are recruited during inflammation (Ramachandran et al., 2012; Willenborg et al., 2012), and not anti-inflammatory CD206+ macrophages (Figure 1B and 1C).”
BackgroundMacrophage Related Chronic Inflammation in Non-Healing Wounds
Li, M., Hou, Q., Zhong, L., Zhao, Y., & Fu, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.681710 · Cited by 307
Macrophages of diverse phenotypes drive vascularization of engineered tissues
Graney, P. L., Ben‐Shaul, S., Landau, S., Bajpai, A., Singh, B. S., Eager, J. M., Cohen, A. R., Levenberg, S., & Spiller, K. L. (2020) · Science Advances · doi:10.1126/sciadv.aay6391 · Cited by 286
Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression
Gurevich, D., Severn, C. E., Twomey, C., Greenhough, A., Cash, J. L., Toye, A., Mellor, H., & Martin, P. (2018) · EMBO Journal · doi:10.15252/embj.201797786 · Cited by 252
“A likely key role for macrophages in wound neoangiogenesis is strongly indicated by their ablation at early time-points following murine wounding, which results in reduced vessel sprouting and aberrant wound angiogenesis (Lucas et al , 2010; Willenborg et al , 2012).”
InfluentialUnraveling macrophage contributions to bone repair
Wu, A. C., Raggatt, L. J., Alexander, K. A., & Pettit, A. R. (2013) · BoneKEy Reports · doi:10.1038/bonekey.2013.107 · Cited by 256
“These pro-angiogenic monocyte/macrophages had a mixed M1 and M2 profile.(48) Macrophages pervading the granulation tissue at a fracture site(12,29) are a confirmed cellular source of VEGFs in soft-tissue injury,(48) and VEGFs have been established as important proangiogenic molecules in fracture repair.”
BackgroundÁlvarez, M. M., Liu, J. C., Santiago, G. T., Cha, B.-H., Vishwakarma, A., Ghaemmaghami, A. M., & Khademhosseini, A. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.01.026 · Cited by 262
Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy
Lechner, A. J., Driver, I. H., Lee, J., Conroy, C., Nagle, A., Locksley, R. M., & Rock, J. R. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.03.024 · Cited by 261
“However, recruitment of CCR2+ monocytes is essential for tissue regeneration in other contexts, including the resolution liver fibrosis and regeneration of the heart and skin (Aurora et al., 2014; Gibbons et al., 2011; Ramachandran et al., 2012; Willenborg et al., 2012).”
Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation
Versey, Z., da Cruz Nizer, W. S., Russell, E., Zigic, S., DeZeeuw, K. G., Marek, J. E., Overhage, J., & Cassol, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.648554 · Cited by 253
Macrophages: A review of their role in wound healing and their therapeutic use
Snyder, R. J., Lantis, J., Kirsner, R. S., Shah, V., Molyneaux, M., & Carter, M. J. (2016) · Wound Repair and Regeneration · doi:10.1111/wrr.12444 · Cited by 245
Organ-Level Quorum Sensing Directs Regeneration in Hair Stem Cell Populations
Chen, C., Wang, L., Plikus, M. V., Jiang, T. X., Murray, P. J., Ramos, R., Guerrero‐Juarez, C. F., Hughes, M. W., Lee, O. K., Shi, S., et al. (2015) · Cell · doi:10.1016/j.cell.2015.02.016 · Cited by 245
“Macrophages can be divided into two major types; M1 macrophages (classi- cally activated) exert proinflammatory activities, and M2 macrophages (alternatively activated) are involved in resolving inflammation (Gordon, 2003; Willenborg et al., 2012).”
Targeting epigenetic mechanisms in diabetic wound healing
den Dekker, A. D., Davis, F. M., Kunkel, S. L., & Gallagher, K. A. (2018) · Translational research · doi:10.1016/j.trsl.2018.10.001 · Cited by 246
“During the normal healing process, macrophages are initially proinflammatory and then transition to an anti-inflammatory phenotype where they promote tissue repair and transition to the next phase of healing.(6,8,9) In diabetic wounds, however, this macrophage transition is altered, causing them to remain in a proinfl…”
Olingy, C. E., Emeterio, C. L. S., Ogle, M. E., Krieger, J. R., Bruce, A. C., Pfau, D. D., Jordan, B. T., Peirce, S. M., & Botchwey, E. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-00477-1 · Cited by 234
“The unique protein signature of non-classical monocytes, characterized by higher VEGF, TGF β , and IL-10, and lower TNF α and IL-1 β expression compared to classical monocytes has resulted in the suggestion that these cells may constitute a class of “anti-inflammatory” monocytes 18, 19 .”
BackgroundInfluentialDisclosure of the culprits: macrophages-versatile regulators of wound healing.
Sindrilaru, A., & Scharffetter-Kochanek, K. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0407 · Cited by 223
“In contrast, the absence of Ly6CCCR2 inflammatory monocytes/macrophages in myeloid-restricted CCR2 deficient mice did not affect overall wound closure despite impairing the early phases of neovascularisation and myofibroblast differentiation.(20) Thus, the early recruitment of Ly6CCCR2 monocytes may reflect an evoluti…”
BackgroundMethodTranscriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing
Lurier, E. B., Dalton, D., Dampier, W., Raman, P., Nassiri, S., Ferraro, N. M., Rajagopalan, R., Sarmady, M., & Spiller, K. L. (2017) · Immunobiology · doi:10.1016/j.imbio.2017.02.006 · Cited by 222
Niu, Y., Wang, Z., Shi, Y., Dong, L., & Wang, C. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.08.012 · Cited by 213
Prostaglandin E2 hydrogel improves cutaneous wound healing via M2 macrophages polarization
Zhang, S., Liu, Y., Zhang, X., Zhu, D., Qi, X., Cao, X., Fang, Y., Che, Y., Han, Z., He, Z., et al. (2018) · Theranostics · doi:10.7150/thno.27385 · Cited by 214
“Numerous studies have shown that macrophages are involved in the regulation of angiogenesis during tissue repair [32-36].”
BackgroundRamírez‐Valle, F., Gray, E. E., & Cyster, J. G. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508990112 · Cited by 213
“C-C chemokine receptor type 2 (CCR2) plays a role in homing of macrophages to inflamed skin and is present on dermal γδT cells (3, 26, 27).”
BackgroundKimball, A., Schaller, M. A., Joshi, A., Davis, F. M., denDekker, A. D., Boniakowski, A. E., Bermick, J., Obi, A. T., Moore, B. B., Henke, P. K., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.310703 · Cited by 216
Clark, A. Y., Martin, K. E., García, J. R., Johnson, C. T., Theriault, H. S., Han, W. M., Zhou, D. W., Botchwey, E. A., & García, A. J. (2020) · Nature Communications · doi:10.1038/s41467-019-14000-9 · Cited by 222
Wang, X., Chen, H., Tian, R., Zhang, Y., Drutskaya, M. S., Wang, C., Ge, J., Fan, Z., Kong, D., Wang, X., et al. (2017) · Nature Communications · doi:10.1038/ncomms14091 · Cited by 211
Altered Macrophage Phenotype Transition Impairs Skeletal Muscle Regeneration
Wang, H., Melton, D. W., Porter, L., Sarwar, Z. U., McManus, L. M., & Shireman, P. K. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.12.020 · Cited by 212
“The American Journal of Pathology based on the cytokine and chemokines production anticipated from M1 macrophages such as IL-1a,46,47 MCP-1,48 51 MCP-3,50,51 MIP-2,3 OSM,52 TNFa,7,47,49,53 and VEGF.5,54 The additional cytokines that were significantly elevated in the Ly6CþCD301 (FGF9, lymphotactin, and SCF) are not co…”
MethodImage based Machine Learning for identification of macrophage subsets
Rostam, H. M., Reynolds, P. M., Alexander, M. R., Gadegaard, N., & Ghaemmaghami, A. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-03780-z · Cited by 196
“These cells have also been shown to express high levels of chemokine (C-C motif) receptor 7 (CCR7) 17 , nitric oxide synthase 2 (NOS2) 18 , calprotectin 19 , and CCR2 20 .”
BackgroundCD11b + Ly6G − myeloid cells mediate mechanical inflammatory pain hypersensitivity
Ghasemlou, N., Chiu, I. M., Julien, J., & Woolf, C. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501372112 · Cited by 196
“Nonneutrophil myeloid cells are primarily responsible for the phagocytosis of debris and invading pathogens in incisional wounds, and, although they are not required for tissue repair, they do play important roles in vascularization, fibrosis, and scarring (37, 68, 69).”
BackgroundCD301b+ Macrophages Are Essential for Effective Skin Wound Healing
Shook, B. A., Xiao, E., Kumamoto, Y., Iwasaki, A., & Horsley, V. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.05.107 · Cited by 186
“After injury, CD11b+/F4-80+ macrophages are recruited to skin in a CCR2-dependent manner and express high levels of Ly6C (Ly6Chi) (Ramachandran et al., 2012; Rodero et al., 2012; Willenborg et al., 2012) and inflammatory cytokines (Eming et al., 2007; Werner and Grose, 2003).”
Macrophages are necessary for epimorphic regeneration in African spiny mice
Simkin, J., Gawriluk, T. R., Gensel, J. C., & Seifert, A. W. (2017) · eLife · doi:10.7554/elife.24623 · Cited by 197
“Whereas CD206+ cells were absent from the blastema in Acomys, in Mus, we observed CD206+ cells throughout the collagen-rich granulation tissue, a situation similar to fibrosis observed during skin wound repair (Mirza and Koh, 2011; Song et al., 2000; Willenborg et al., 2012).”
BackgroundMia, M. M., Cibi, D. M., Ghani, S. A. B. A., Song, W., Tee, N., Ghosh, S., Mao, J., Olson, E. N., & Singh, M. K. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000941 · Cited by 186
“Using a reporter mouse line, Willenborg and colleagues demonstrated that Vegf expression by macrophages is required to induce capillary sprouting during wound healing [73].”
BackgroundWound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities
Bukowiecki, A., Hos, D., Cursiefen, C., & Eming, S. A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061257 · Cited by 184
“recruitment of VEGF-A-expressing macrophages is critical for the initiation of capillary sprouting during the wound healing response [174].”
BackgroundOvermeire, E. V., Laoui, D., Keirsse, J., Ginderachter, J. A. V., & Sarukhan, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00127 · Cited by 186
“This is expected to be especially prominent under (chronic) inflammatory conditions and injury, during which the tissue macrophage pool is typically reinforced by the influx of monocytes, as demonstrated in liver (34), skin (35, 36), brain (37), colon (38), and other tissues.”
BackgroundSaldaña, L., Bensiamar, F., Vallés, G., Mancebo, F. J., García‐Rey, E., & Vilaboa, N. E. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1156-6 · Cited by 174
Differential gene expression in human, murine, and cell line-derived macrophages upon polarization
Spiller, K. L., Wrona, E. A., Romero‐Torres, S., Pallotta, I., Graney, P. L., Witherel, C. E., Panicker, L. M., Feldman, R. A., Urbanska, A. M., Santambrogio, L., et al. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.10.017 · Cited by 170
“6 phenotype promoting angiogenesis [19, 20], while other studies have shown that M1 macrophages are more angiogenic [16, 21].”
BackgroundMacrophage Dysregulation and Impaired Skin Wound Healing in Diabetes
Barman, P. K., & Koh, T. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00528 · Cited by 175
“In addition, wound Mo/Mφ are an important source of growth factors such as VEGF, which is critical for angiogenesis and tissue growth (Stockmann et al., 2011; Willenborg et al., 2012).”
BackgroundHsieh, C. L., Niemi, E. C., Wang, S. H., Lee, C. C., Bingham, D., Zhang, J., Cozen, M. L., Charo, I., Huang, E. J., Liu, J., et al. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2013.3252 · Cited by 174
Jacome-Galarza, C. E., Lee, S., Lorenzo, J., & Aguila, H. L. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1822 · Cited by 160
IL-4 and IL-13: Regulators and Effectors of Wound Repair
Allen, J. E. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101921-041206 · Cited by 158
Monocyte-endothelial cell interactions in vascular and tissue remodeling
Medrano-Bosch, M., Simón-Codina, B., Jiménez, W., Edelman, E. R., & Melgar‐Lesmes, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1196033 · Cited by 168
Okizaki, S.-I., Ito, Y., Hosono, K., Oba, K., Ohkubo, H., Amano, H., Shichiri, M., & Majima, M. (2014) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2014.10.020 · Cited by 150
Role of Macrophages in Wound HealingPreprint
Willenborg, S., Injarabian, L., & Eming, S. A. (2022) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041216 · Cited by 150
Awojoodu, A. O., Ogle, M. E., Sefcik, L. S., Bowers, D. T., Martin, K. S., Brayman, K. L., Lynch, K. R., Peirce, S. M., & Botchwey, E. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221309110 · Cited by 147
“Similarly, in the spinotrapezius model in vessels surrounding FTY720-loaded PLAGA scaffolds in ischemic muscle, there was a significant increase in cells expressing CX3CR1, possibly owing to increased SDF-1α in response to ischemia (25).”
BackgroundResultOsteomacs and Bone Regeneration
Batoon, L., Millard, S. M., Raggatt, L. J., & Pettit, A. R. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0384-x · Cited by 148
The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited
Dzobo, K., Senthebane, D. A., & Dandara, C. (2023) · Cancers · doi:10.3390/cancers15020376 · Cited by 146
Bannon, P., Wood, S., Restivo, T., Campbell, L., Hardman, M., & Mace, K. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.012237 · Cited by 154
“Recent studies suggest that CCR2+ M1/M2 mixed-phenotype myeloid cells make up the majority of pro-angiogenic macrophages during wound healing and, consistent with our data, are present at early wound time points (Willenborg et al., 2012).”
Wermuth, P. J., & Jiménez, S. A. (2015) · Clinical and Translational Medicine · doi:10.1186/s40169-015-0047-4 · Cited by 141
“numbers with a concomitant increase of Ly6C monocytes [17-24].”
BackgroundKim, Y., Furuya, H., & Tabata, Y. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.09.103 · Cited by 142
“The deficiency of macrophages at tissue defects delayed the process of the tissue regeneration because macrophages play a important role in the phagocytosis or removal of pathogen and initiation of relative gene expression for tissues repairing [11, 49].”
BackgroundCCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells
Feng, G., Bajpai, G., Ma, P., Koenig, A. L., Bredemeyer, A. L., Lokshina, I., Lai, L., Förster, I., Leuschner, F., Kreisel, D., et al. (2022) · Circulation · doi:10.1161/circulationaha.121.055888 · Cited by 143
Mantsounga, C., Lee, C. F., Neverson, J., Sharma, S., Healy, A. L., Berus, J. M., Parry, C., Ceneri, N. M., López‐Giráldez, F., Chun, H. J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110309 · Cited by 143
“In humans, this inflammatory macrophage population is characterized by the high expression of the chemokine receptor, C-C motif chemokine receptor 2 (CCR2), and the lipopolysaccharide (LPS) co-receptor, CD14, inducible nitric oxide synthase (NOS2), interleukin-1 β (IL-1 β ), and interleukin-6 (IL-6) (Willenborg et al.…”
InfluentialNakkala, J. R., Li, Z., Ahmad, W., Wang, K., & Gao, C. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.01.025 · Cited by 136
Heparin desulfation modulates VEGF release and angiogenesis in diabetic wounds
Freudenberg, U., Zieris, A., Chwalek, K., Tsurkan, M. V., Maitz, M. F., Atallah, P., Levental, K. R., Eming, S. A., & Werner, C. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.10.028 · Cited by 130
He, L., & Marneros, A. G. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.02.032 · Cited by 126
“Efficient Cremediated excision of the floxed VEGF-A allele in myeloid cells with lysozyme M Cre mice has been demonstrated.(17,18) Cre expression in RPE cells that are homozygous for the floxed VEGF-A was assessed by immunolabeling for Cre using a monoclonal mouse antiCre antibody (clone 2D8; EMD Millipore, Billerica,…”
MethodResultInfluentialBoniakowski, A. E., Kimball, A., Joshi, A., Schaller, M., Davis, F. M., denDekker, A. D., Obi, A. T., Moore, B. B., Kunkel, S. L., & Gallagher, K. A. (2018) · European Journal of Immunology · doi:10.1002/eji.201747400 · Cited by 130
Innate Immunity in Diabetic Wound Healing: Focus on the Mastermind Hidden in Chronic Inflammatory
Geng, K., Ma, X., Jiang, Z., Huang, W. G., Gao, C., Pu, Y., Luo, L., Xu, Y., & Xu, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.653940 · Cited by 125
Sidibé, A., Ropraz, P., Jemelin, S., Emre, Y., Poittevin, M., Pocard, M. D., Bradfield, P. F., & Imhof, B. A. (2018) · Nature Communications · doi:10.1038/s41467-017-02610-0 · Cited by 121
Little, K., Jacey, H., Yang, N., Chen, M., & Xu, H. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.11.029 · Cited by 118
“For example, RPE, microglia and macrophages can all produce CCL2, a chemokine that plays an important role in the recruitment of CCR2 macrophages [48] and fibrocytes [49].”
BackgroundThe impact of surface chemistry modification on macrophage polarisation
Rostam, H. M., Singh, S., Salazar, F., Magennis, E. P., Hook, A. L., Singh, T., Vrana, N. E., Alexander, M. R., & Ghaemmaghami, A. M. (2016) · Immunobiology · doi:10.1016/j.imbio.2016.06.010 · Cited by 117
The role of macrophages in skin homeostasis
Yanez, D. A., Lacher, R. K., Vidyarthi, A., & Colegio, O. R. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1953-7 · Cited by 117
“Moreover, phagocytosis of apoptotic cells by macrophages leads to the production of VEGF-A [17], which induces vascularization and tissue regeneration [77].”
Toll-Like Receptor Function in Acute Wounds
Chen, L., & DiPietro, L. A. (2017) · Advances in Wound Care · doi:10.1089/wound.2017.0734 · Cited by 121
“reaction, help recruit more inflammatory cells, and promote the proliferative phase of repair, including angiogenesis and tissue regrowth.(19,24,25) Multiple studies now demonstrate that macrophages play an indispensable role in wound healing.”
Burgess, M. O., Wicks, K., Gardasevic, M., & Mace, K. A. (2019) · ImmunoHorizons · doi:10.4049/immunohorizons.1900038 · Cited by 119
“Our results support previous analyses of classically activated and alternatively activated macrophages in skin in which CCR2 macrophages recruited from BM were the predominant macrophage subtype present and initially showed a classically activated phenotype, playing a critical role during the early inflammatory stages…”
ResultLaurent, F., & Lacroix‐Lamandé, S. (2017) · International Journal for Parasitology · doi:10.1016/j.ijpara.2017.08.001 · Cited by 112
“However, in addition to impaired recruitment via CCR2, CCR2-/-mice exhibit impaired egress of Ly6c+ monocytes from the bone marrow (Egan et al., 2009; Platt et al., 2010; Willenborg et al., 2012).”
BackgroundPedragosa, J., Miró‐Mur, F., Otxoa-de-Amezaga, A., Justicia, C., Ruíz-Jaén, F., Ponsaerts, P., Pasparakis, M., & Planas, A. M. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20909055 · Cited by 115
“CCR2-deficiency in monocytes reduces monocyte infiltration to the ischemic brain tissue without affecting the recruitment of other leukocytes To investigate the function of infiltrating CCR2þ monocytes we induced selective CCR2 deletion in myeloid cells by crossing LysMcreþ mice with floxed Ccr2 (Ccr2) mice (Figure 2(…”
BackgroundMethodInfluentialPlatelet Derivatives and the Immunomodulation of Wound Healing
Scopelliti, F., Cattani, C., Dimartino, V., Mirisola, C., & Cavani, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158370 · Cited by 119
Jiang, D., Qi, Y., Walker, N. G., Sindrilaru, A., Hainzl, A., Wlaschek, M., MacNeil, S., & Scharffetter‐Kochanek, K. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2012.12.014 · Cited by 112
Temporal changes in macrophage phenotype after peripheral nerve injury
Tomlinson, J. E., Žygelytė, E., Grenier, J. K., Edwards, M. G., & Cheetham, J. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1219-0 · Cited by 112
Controlled M1-to-M2 transition of aged macrophages by calcium phosphate coatings
Alhamdi, J. R., Peng, T., Al-Naggar, I. M., Hawley, K. L., Spiller, K. L., & Kuhn, L. T. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2018.07.012 · Cited by 110
“Furthermore, given the ability of M1 macrophages to s imulate angiogenesis during tissue regeneration (78, 79), the enhanced M1 macrophage p henotype induced by the bCaP coating may contribute positively to tissue repair.”
Rehak, L., Giurato, L., Meloni, M., Panunzi, A., Manti, G. M., & Uccioli, L. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030889 · Cited by 112
“During this phase, both M1 and M2 are also responsible for the vascularization process, first creating new vessels trough sprouting [40], then creating anastomoses between newly formed vessels [41].”
BackgroundModelling skin wound healing angiogenesis: A review
Guerra, A., Belinha, J., & Jorge, R. N. (2018) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2018.09.020 · Cited by 116
Macrophage regulation of angiogenesis in health and disease
Martin, P. B., & Gurevich, D. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.06.010 · Cited by 114
“These macrophages express high levels of typically pro-inflammatory M1 markers, IL6 and iNOS, but also expressed the more anti-inflammatory M2 related TIE2 receptor [9].”
BackgroundA monocyte–leptin–angiogenesis pathway critical for repair post-infection
Kratofil, R. M., Shim, H. B., Shim, R., Lee, W.-Y., Labit, E., Sinha, S., Keenan, C. M., Surewaard, B. G. J., Noh, J. Y., Sun, Y., et al. (2022) · Nature · doi:10.1038/s41586-022-05044-x · Cited by 105
In Situ Tissue Engineering of Functional Small-Diameter Blood Vessels by Host Circulating Cells Only
Talacua, H., Smits, A. I. P. M., Muylaert, D. E. P., van Rijswijk, J. W., Vink, A., Verhaar, M. C., Driessen‐Mol, A., van Herwerden, L. A., Bouten, C. V. C., Kluin, J., et al. (2015) · Tissue Engineering Part A · doi:10.1089/ten.tea.2015.0066 · Cited by 106
“8,26,27 Monocyte and macrophage trafficking was shown to be dependent on MCP-1 and its primary receptor, CCR2.”
Endothelial progenitor cell: a blood cell by many other names may serve similar functions
Yöder, M. C. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1002-8 · Cited by 105
“A sampling of recent work reveals that different monocyte subsets appear more readily specified to proangiogenic macrophage fates [114–116], are key components of the tumor microenvironment [117, 118], can be targeted for specific antitumor angiogenic responses [119–121], employ both Wnt [122] and Notch [123–125] sign…”
BackgroundRodriguez-Menocal, L., Shareef, S., Salgado, M., Shabbir, A., & Badiavas, E. V. (2015) · Stem Cell Research & Therapy · doi:10.1186/s13287-015-0001-9 · Cited by 102
“Some reports suggest that certain bone marrow derived cells, such as mesenchymal stem cells, secrete a broad spectrum of angiogenic or anti-apoptotic cytokines, which play a role in the process of tissue repair and that BMMSC conditioned medium has been shown to contain the majority of human cytokines fundamental in w…”
BackgroundNotch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing
Kimball, A., Joshi, A., Boniakowski, A. E., Schaller, M. A., Chung, J., Allen, R., Bermick, J., Carson, W. F., Henke, P. K., Maillard, I. P., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00635 · Cited by 101
“For example, canonical Notch signaling and vascular endothelial growth factor-A (VEGF-A) are known to play a role in angiogenesis in both tumors and injured tissue, while simultaneously VEGF-A is known to be secreted by infiltrating inflammatory monocytes (25, 43, 44).”
Background
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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