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 both macrophage-depletion conditions, progression to the following phases of wound repair fails.
“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]
Absence of macrophages in the inflammatory phase reduces re-epithelialization and granulation tissue formation.
“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]
Depletion of macrophages in the proliferative phase results in haemorrhage.
“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]
Depletion of macrophages during the proliferative phase of wound healing results in a defective transition to the remodeling phase and impaired healing.
“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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“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…”
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“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
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“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
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Macrophage Related Chronic Inflammation in Non-Healing Wounds
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“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
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“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).”
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“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
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“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
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“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
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“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. J., Jayaraman, V., Huelsmann, E., Bonish, B., Burgad, D., Sivaramakrishnan, G., Qin, S., DiPietro, L., Zloza, A., Zhang, C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091574 · Cited by 252 · see citing works
“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 · see citing works
“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
- 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 › Rehabilitation › 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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