The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Differential Roles of Macrophages in Diverse Phases of Skin Repair
Abstract
Influx of macrophages plays a crucial role in tissue repair. However, the precise function of macrophages during the healing response has remained a subject of debate due to their functional dichotomy as effectors of both tissue injury and repair. We tested the hypothesis that macrophages recruited during the diverse phases of skin repair after mechanical injury exert specific functions to restore tissue integrity. For this purpose, we developed a mouse model that allows conditional depletion of macrophages during the sequential stages of the repair response. Depletion of macrophages restricted to the early stage of the repair response (inflammatory phase) significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimized scar formation. In contrast, depletion of macrophages restricted to the consecutive mid-stage of the repair response (phase of tissue formation) resulted in severe hemorrhage in the wound tissue. Under these conditions, transition into the subsequent phase of tissue maturation and wound closure did not occur. Finally, macrophage depletion restricted to the late stage of repair (phase of tissue maturation) did not significantly impact the outcome of the repair response. These results demonstrate that macrophages exert distinct functions during the diverse phases of skin repair, which are crucial to control the natural sequence of repair events.
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In the citing paper
“In both conditions, progression to the following phases of wound repair fails [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“Their study shows that when macrophages are absent in the inflammatory phase, re-epithelialization and granulation tissue formation are reduced; whereas depletion of macrophages in the proliferative phase results in haemorrhage [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“Their study shows that when macrophages are absent in the inflammatory phase, re-epithelialization and granulation tissue formation are reduced; whereas depletion of macrophages in the proliferative phase results in haemorrhage [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“A recent study showed that depletion of macrophages during the proliferative phase of wound healing resulted in a defective transition to the remodeling phase and impaired healing [106,107].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [106]
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Macrophage plasticity and polarization: in vivo veritas
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Self-citationWound Healing: A Cellular Perspective
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“Depletion studies similar to the ones examining the role of macrophages during different phases of repair after skin injury have also not been performed after SCI (Lucas et al., 2010).”
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Self-citationMyofibroblast proliferation and heterogeneity are supported by macrophages during skin repair
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BackgroundResultMacrophage-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
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Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing
Nosbaum, A., Prevel, N., Truong, H.-A., Mehta, P., Ettinger, M., Scharschmidt, T. C., Ali, N. H., Pauli, M. L., Abbas, A. K., & Rosenblum, M. D. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502139 · Cited by 418
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The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication
Pakshir, P., & Hinz, B. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.01.019 · Cited by 396
The initiation of oxidative stress and therapeutic strategies in wound healing
Wang, G., Yang, F., Zhou, W., Xiao, N., Luo, M., & Tang, Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114004 · Cited by 451
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
“Macrophages are cells of a great importance for the process of healing [3, 49, 55, 56].”
BackgroundMonocyte Conversion During Inflammation and Injury
Kratofil, R. M., Kubes, P., & Deniset, J. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308198 · Cited by 536
Redox control of inflammation in macrophages
Brüne, B., Dehne, N., Grossmann, N., Jung, M., Namgaladze, D., Schmid, T., von Knethen, A., & Weigert, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4785 · Cited by 377
“Accordingly, macrophage depletion shortly after introducing skin wounds in mice resulted in delayed re-epithelization and angiogenesis, as well as prolonged inflammation (177).”
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
“Several recent studies have examined macrophage subpopulations in vivo using markers of the M2a phenotype to distinguish M1 from M2 macrophages [3, 20–24].”
InfluentialMSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing
He, X., Dong, Z., Cao, Y., Wang, H., Liu, S., Liao, L., Jin, Y. J., Yuan, L., & Li, B. (2019) · Stem Cells International · doi:10.1155/2019/7132708 · Cited by 417
“The inflammatory response is a crucial component of cutaneous wound healing, as evidenced by severely delayed repair following in vivomacrophage ablation [6].”
Macrophages modulate adult zebrafish tail fin regeneration
Petrie, T. A., Strand, N. S., Tsung-Yang, C., Rabinowitz, J. S., & Moon, R. T. (2014) · Development · doi:10.1242/dev.098459 · Cited by 365
“Although mammalian macrophages serve unique, specific functions at distinct phases during tissue repair (Liu et al., 1999; Lucas et al., 2010), zebrafish macrophages seem to function differently at analogous stages after wounding.”
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
“demonstrated that VEGF-A expression by monocyte-derived CCR2Ly6C macrophages is required for the induction of capillary sprouting in the setting of skin wound healing [171,298].”
BackgroundThe Roles of Inflammation in Keloid and Hypertrophic Scars
Wang, Z., Zhao, W.-Y., Cao, Y., Liu, Y., Sun, Q., Shi, P. D., Cai, J., Shen, X. Z., & Tan, W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.603187 · Cited by 395
“Early macrophage depletion showed benefits in minimizing scar formation (11), while BTX A treatment improved scar quality but had negligible effect on scar size (60, 76).”
BackgroundEvolution of Th2 Immunity: A Rapid Repair Response to Tissue Destructive Pathogens
Allen, J. E., & Wynn, T. A. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002003 · Cited by 351
“Recently, Lucas and colleagues [13] demonstrated that macrophages recruited during the early inflammatory stages of a sterile skin wound expressed Th2 activation markers and that macrophage depletion in the first 5 days significantly delayed the rate of repair but also resulted in less scar tissue.”
BackgroundThe Healing Power of Neutrophils
Phillipson, M., & Kubes, P. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.05.001 · Cited by 398
The Multitasking Organ: Recent Insights into Skin Immune Function
Meglio, P. D., Perera, G. K., & Nestle, F. O. (2011) · Immunity · doi:10.1016/j.immuni.2011.12.003 · Cited by 370
Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice
Mirza, R., & Koh, T. J. (2011) · Cytokine · doi:10.1016/j.cyto.2011.06.016 · Cited by 342
Vasandan, A. B., Jahnavi, S., Chandanala, S., Prasad, P., Kumar, A., & Prasanna, S. J. (2016) · Scientific Reports · doi:10.1038/srep38308 · Cited by 415
Phenotypic 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
“Although cell proliferation and angiogenesis appear to be initiated by monocytes/macrophages of the inflammatory phase, depletion of macrophages during the proliferative phase of mouse skin wound healing indicates that these macrophages support survival of endothelial cells and initiate transition of granulation tissu…”
BackgroundInfluentialde Souza, H. D., Tortori, C., Lintomen, L., Figueiredo, R., Bernardazzi, C., Leng, L., Bucala, R., Madi, K., Buongusto, F., Elia, C., et al. (2015) · Mucosal Immunology · doi:10.1038/mi.2015.6 · Cited by 324
“Macrophages further coordinate wound closure by secreting cytokines and growth factors that play a pivotal role in restructuring of the wound bed with accompanying matrix reorganization, angiogenesis, and epithelial barrier repair.(97) One important cytokine in this regard is TGF-b.”
Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing
Sawaya, A. P., Stone, R. C., Brooks, S. R., Pastar, I., Jozic, I., Hasneen, K., O’Neill, K. E., Mehdizadeh, S., Head, C. R., Štrbo, N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18276-0 · Cited by 376
Mirza, 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
“Mp promote tissue repair by killing pathogens, clearing damaged tissue and producing growth factors that induce angiogenesis, collagen deposition and wound closure (4; 8-11).”
BackgroundInterleukin-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
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Self-citationAdult Zebrafish as a Model System for Cutaneous Wound-Healing Research
Richardson, R., Slanchev, K., Kraus, C., Knyphausen, P., Eming, S., & Hammerschmidt, M. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.16 · Cited by 299
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Macrophage reaction against biomaterials in the mouse model–phenotypes, functions and markers
Klopfleisch, R. (2016) · Acta Biomaterialia · doi:10.1016/j.actbio.2016.07.003 · Cited by 298
Qiu, P., Li, M., Chen, K., Fang, B., Chen, P., Tang, Z., Lin, X., & Fan, S. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119552 · Cited by 340
Extracellular matrix contribution to skin wound re-epithelialization
Rousselle, P., Montmasson, M., & Garnier, C. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.01.002 · Cited by 357
The production and application of hydrogels for wound management: A review
Gupta, A., Kowalczuk, M. M., Heaselgrave, W., Britland, S. T., Martin, C., & Radecka, I. (2018) · European Polymer Journal · doi:10.1016/j.eurpolymj.2018.12.019 · Cited by 349
Immune Modulation of Stem Cells and Regeneration
Aurora, A. B., & Olson, E. N. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.06.009 · Cited by 322
Macrophages: Supportive cells for tissue repair and regeneration
Chazaud, B. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.09.001 · Cited by 326
“macrophages sustain tissue repair and/or regeneration (Lucas et al., 2010).”
Macrophage 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
“And the selective depletion of macrophage at different stages of wound repair implied that macrophages took on distinct roles throughout the healing process (34).”
BackgroundThe Promise of Targeting Macrophages in Cancer Therapy
Brown, J. M., Recht, L. D., & Strober, S. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3122 · Cited by 326
“Later,macrophages further coordinate wound closure by secreting cytokines and growth factors, including TGFb, that play a pivotal role in restructuring the wound bed with accompanying matrix reorganization and epithelial barrier repair (22).”
BackgroundAge-Related Aspects of Cutaneous Wound Healing: A Mini-Review
Sgonc, R., & Gruber, J. (2013) · Gerontology · doi:10.1159/000342344 · Cited by 288
Macrophage-based therapeutic strategies in regenerative medicine
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Macrophages prevent hemorrhagic infarct transformation in murine stroke models
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Tumor Promotion via Injury- and Death-Induced Inflammation
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“Macrophage activation and polarization is crucial in the coordination of the later inflammation and regeneration phases.(95,96) Thus, macrophage polarization and activation is at the forefront of scientific investigation, with various studies aiming to modulate it using biophysical cues (e.”
BackgroundRaggatt, L. J., Wullschleger, M., Alexander, K. A., Wu, A., Millard, S. M., Kaur, S., Maugham, M., Gregory, L. S., Steck, R., & Pettit, A. R. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.08.017 · Cited by 292
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
“While ablating macrophages throughout wound healing has been shown to impair all reparative processes (Clausen et al., 1999; Goren et al., 2010; Lucas et al., 2010; Mirza et al., 2010; Shook et al., 2016), ablating dermal adipocytes reduced revascularization by 66% throughout the entire wound bed and re-epithelializat…”
BackgroundAbnormal Cell Responses and Role of TNF- α in Impaired Diabetic Wound Healing
Xu, F., Zhang, C., & Graves, D. T. (2013) · BioMed Research International · doi:10.1155/2013/754802 · Cited by 238
“Depletion of macrophages during the in�ammatory phase results in signi�cant delay of wound repair in a mouse model [28].”
BackgroundUnraveling 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
“Overall, the polarization phenotype adopted by a macrophage can have a major influence over healing progression and outcome.(19) We”
BackgroundLive 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).”
InfluentialWood, S., Jayaraman, V., Huelsmann, E. J., Bonish, B. K., Burgad, D., Sivaramakrishnan, G., Qin, S., DiPietro, L. A., Zloza, A., Zhang, C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091574 · Cited by 256
“Given the importance of macrophages for the process of healing [7–11] and their potential role in pathology associated with”
Van De Water, L., Varney, S., & Tomasek, J. J. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0393 · Cited by 251
“One important determinant, recently identified, is the switch in macrophage ‘‘class’’ from the M1 (inflammatory) phenotype to the M2 (resolution) phenotype.(63) Fibroblasts migrating in the provisional matrix of the early granulation tissue exhibit increased F-actin staining and EDA-positive FN staining a few days ahe…”
Background
Metadata
- Authors
- Lucas, T., Waisman, A., Ranjan, R., Roes, J., Krieg, T., Müller, W., Roers, A., & Eming, S. A.
- Affiliations
- Department of Dermatology
- Johannes Gutenberg University Mainz (DE)
- University College London (GB)
- University of Cologne (DE)
- University of Manchester (GB)
- Technische Universität Dresden (DE)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-01
- Volume
- 184
- Issue
- 7
- Pages
- 3964-3977
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2118654016
- Cited by
- 1,205
- References
- 0
- Citations by year
- 2026: 47 · 2025: 71 · 2024: 84 · 2023: 86 · 2022: 110 · 2021: 102 · 2020: 90 · 2019: 76 · 2018: 87 · 2017: 83 · 2016: 73 · 2015: 78 · 2014: 73 · 2013: 66 · 2012: 41
- FWCI
- 47.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- University College London
- Deutsche Forschungsgemeinschaft (SFB829)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- macrophages, skin repair, wound healing, mechanical damage, granulation tissue, re-epithelialization, scar formation, hemorrhage, tissue maturation, wound closure, tissue formation
- MeSH terms
- Animals, Cell Separation, Flow Cytometry, Immunohistochemistry, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Skin, Skin Physiological Phenomena, Wound Healing, Reverse Transcriptase Polymerase Chain Reaction, Mice
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