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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Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E 2
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Platelet-Rich Plasma Injection With Arthroscopic Acromioplasty for Chronic Rotator Cuff Tendinopathy
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“Macrophages exert different roles at diverse stages of the repair response, and they orchestrate the natural sequence of repair phases in skin, which are essential to restore solid tissue homeostasis and integrity after injury [”
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“However, in chronic wounds, sustained M1 polarization reduces VEGF and fibroblast growth factor levels, while inflammatory mediators (e.g., TNF-α and IL-1) further suppress endothelial cell activity [79], collectively impairing neovascularization [80, 81].”
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“During chronic inflammation, there is strong evidence for an inappropriate persistence of M1 macrophages, which are directly associated with the development and perpetuation of many chronic inflammatory and autoimmune diseases.(8,35) In rheumatoid arthritis, crosstalk between M1 and Th17 cells is implicated in severit…”
BackgroundImproved repair of dermal wounds in mice lacking micro RNA‐155
van Solingen, C., Araldi, E., Chamorro‐Jorganes, A., Fernández‐Hernando, C., & Suárez, Y. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12255 · Cited by 66
“mice depleted of macrophages in early or mid-stages of wound healing have defective wound repair [9, 10].”
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“Lucas et al. (110) used a temporal depletion strategy to examine the stage-specific contribution of macrophages to repair.”
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“However, macrophage depletion during the late phase of wound healing did not affect the overall process.(111) Interestingly, a similar result has been observed in axolotl limb regeneration, where the early depletion of macrophages results in a lack of regeneration but later depletion has no significant impact on regen…”
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“M2 macrophages are generally associated with tissue repair (Lucas et al., 2010; Sica and Mantovani, 2012).”
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BackgroundSelective M2 Macrophage Depletion Leads to Prolonged Inflammation in Surgical Wounds
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“At the same time, severe early inhibition of macrophage signaling (as well as macrophage ablation during later stages of inflammation) results in delayed healing in mouse wound models (62, 63), suggesting that initial macrophage availability (and, therefore, their sufficient influx) is necessary for normal inflammator…”
BackgroundCalpain Activity Is Essential in Skin Wound Healing and Contributes to Scar Formation
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Franklin, R. A. (2021) · Immunological Reviews · doi:10.1111/imr.12989 · Cited by 71
The complex TIE between macrophages and angiogenesis
Cheyne, C. D., Tay, H., & Spiegelaere, W. D. (2019) · Anatomia, Histologia, Embryologia. Journal of Veterinary Medicine Series C · doi:10.1111/ahe.12518 · Cited by 63
Macrophages are necessary for skin regeneration during tissue expansion
Ding, J., Lei, L., Liu, S., Zhang, Y., Yu, Z., Su, Y., & Ma, X. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1780-z · Cited by 68
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Macrophage polarization in tissue fibrosis
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“A shift from M1 to M2 was described in the wound healing processes from inflammation to restoration ( Duffield et al., 2005 ; Gibbons et al., 2011 ; Lucas et al., 2010 ).”
BackgroundLiu, Y., Zhang, X., Yang, L., Zhou, S., Li, Y., Shen, Y., Lu, S., Zhou, J., & Liu, Y. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154892 · Cited by 62
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Regulation of the Wound Healing Response during Aging
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Self-citationDetermining the effector response to cell death
Rothlin, C. V., Hille, T. D., & Ghosh, S. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00456-0 · Cited by 69
Chen, L., Wang, J., Li, S.-X., Yu, Z., Liu, B., Song, B.-Q., & Su, Y.-J. (2018) · International Wound Journal · doi:10.1111/iwj.13041 · Cited by 61
“A recent study showed that the depletion of macrophages restricted to the early stage of the repair response resulted in minimised scar formation; in contrast, the depletion of macrophages restricted the consecutive midstage of the repair response and the late stage of repair did not significantly impact the outcome o…”
BackgroundResultBiomaterials for revascularization and immunomodulation after spinal cord injury
Haggerty, A. E., Maldonado, I. C., & Oudega, M. (2018) · Biomedical Materials · doi:10.1088/1748-605x/aaa9d8 · Cited by 74
Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis
Soundia, A., Hadaya, D., Esfandi, N., Gkouveris, I., Christensen, R., Dry, S. M., Bezouglaia, O., Pirih, F., Nikitakis, N. G., Aghaloo, T., et al. (2018) · Journal of dentistry research · doi:10.1177/0022034517732770 · Cited by 61
“Subsequently, at the maturation phase, granulation tissue develops into fibrotic tissue, marked by replacement of the provisional matrix with collagen (Lucas et al. 2010).”
BackgroundKlar, A. S., Michalak-Micka, K., Biedermann, T., Simmen-Meuli, C., Reichmann, E., & Meuli, M. (2018) · Pediatric surgery international (Print) · doi:10.1007/s00383-017-4179-z · Cited by 61
“Interestingly, the depletion of pro-inflammatory macrophages was shown to reduce scar formation in the skin [24].”
BackgroundOkizaki, S.-I., Ito, Y., Hosono, K., Oba, K., Ohkubo, H., Kojo, K., Nishizawa, N., Shibuya, M., Shichiri, M., & Majima, M. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.02.014 · Cited by 64
Skin wound healing in different aged Xenopus laevis
Bertolotti, E., Malagoli, D., & Franchini, A. (2013) · Journal of Morphology · doi:10.1002/jmor.20155 · Cited by 60
Crosstalk between mesenchymal stem cells and macrophages in tissue repair
Chung, E., & Son, Y. (2014) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-014-0072-1 · Cited by 60
“The delay was accompanied by reduced formation of vascularized granulation tissues, impaired epithelialization, and minimized scar formation with attenuated angiogenesis and myofibroblast differentiation.(30) Although the interplay or contribution of MSCs in the studies on macrophage depletion in skin injury has not b…”
Skin immunity in wound healing and cancer
Jakovija, A., & Chtanova, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1060258 · Cited by 70
“At least three functional subsets of macrophages contribute to the different stages of wound healing and tissue repair: (i) pro‐ inflammatory (traditionally referred to as “M1”), (ii) tissue repair or pro-wound healing, and (iii) anti‐inflammatory or pro-resolving macrophages (91, 92).”
BackgroundYou, S., Zhu, Y., Li, H., He, F., Liu, S., Yang, X., Wang, L., Zeng, H., Dai, J.-C., & Hu, L. (2023) · Regenerative Biomaterials · doi:10.1093/rb/rbad033 · Cited by 59
“Macrophages are closely connected with immune regulation and tissue regeneration, and they also play a vital role in endometrium regeneration during menstruation and endometrial receptivity establishment during successful pregnancy [15, 62–68].”
IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation
Chao, H., Zheng, L., Hsu, P., He, J., Wu, R., Xu, S., Zeng, R., Zhou, Y., Ma, H., Liu, H., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.157091 · Cited by 66
Oryan, A., Alemzadeh, E., & Eskandari, M. (2018) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-018-9435-6 · Cited by 59
Macrophage Depletion Impairs Corneal Wound Healing after Autologous Transplantation in Mice
Li, S., Li, B., (402726), H. J., Wang, Y., Qu, M., Duan, H., Zhou, Q., & Shi, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061799 · Cited by 62
“Macrophages have been confirmed to play a central role during all phases of wound healing [24,25].”
BackgroundRegulatory macrophages as therapeutic targets and therapeutic agents in solid organ transplantation
Broichhausen, C., Riquelme, P., Geissler, E. K., & Hutchinson, J. A. (2012) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e328355a979 · Cited by 59
“The conditions that dictate whether macrophages in vivo switch to a quiescent state and help to restore tissue homeostasis, or remain in an activated condition and promote chronic inflammation, are presently not well understood [18,19].”
Matrix Metalloproteinases and Leukocyte Activation
Smigiel, K. S., & Parks, W. C. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.01.003 · Cited by 77
The cell biology of inflammation: From common traits to remarkable immunological adaptations
Weavers, H., & Martin, P. B. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202004003 · Cited by 68
“Conditional knockdown of macrophages at various time points following murine wounding leads to a series of repair defects that support the idea of macrophages having a number of different functions at various phases during the repair process (Lucas et al., 2010).”
BackgroundHost–Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection
King, I. L., & Li, Y. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02128 · Cited by 81
“This work has been recently supported and expanded upon in human vascular disease (26), a zebrafish model of tissue regeneration (27) and mouse models of acute skin (28), liver (29), and muscle injuries (30) where IL-4/IL-13 signals promote clearance of cellular debris and tissue healing by structural cells and AAMacs.”
BackgroundWallace, H., Fear, M., Crowe, M., Martin, L., & Wood, F. (2017) · Burns · doi:10.1016/j.burns.2017.03.017 · Cited by 58
The cellular and molecular determinants of emphysematous destruction in COPD
Suzuki, M., Sze, M. A., Campbell, J. D., Brothers, J. F., Lenburg, M. E., McDonough, J. E., Elliott, W. M., Cooper, J. D., Spira, A. E., & Hogg, J. C. (2017) · Scientific Reports · doi:10.1038/s41598-017-10126-2 · Cited by 64
The Role of Adipocytes in Tissue Regeneration and Stem Cell Niches
Shook, B. A., Rivera-Gonzalez, G. C., Ebmeier, S., Grisotti, G., Zwick, R. K., & Horsley, V. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-125426 · Cited by 59
“Given the importance of inflammatory cytokines and macrophage phenotype in regenerative processes in many tissues after injury (Goren et al. 2010, Lucas et al. 2010, Sciorati et al. 2016), the impact of adipocytes on macrophage phenotype may influence tissue regeneration more broadly.”
BackgroundMacrophages promote epithelial repair through hepatocyte growth factor secretion
D'Angelo, F., Bernasconi, E., Schäfer, M., Moyat, M., Michetti, P., Maillard, M., & Velin, D. (2013) · Clinical and Experimental Immunology · doi:10.1111/cei.12157 · Cited by 58
“Macrophages have been shown to play major roles in several aspects that are essential for efficient wound repair [1–3].”
Zhang, X., Song, W. D., Liu, Y., Han, K., Wu, Y., Cho, E., Fang, Z., Jiang, L., Hu, Y., Zhu, X., et al. (2024) · Small · doi:10.1002/smll.202311033 · Cited by 54
Inflammation as an orchestrator of cutaneous scar formation: a review of the literature
abnormal, K. A., tumors, R. S. T. D. A. I. T. S. D. S. S. W., disease, A. T. T. T. I. T. A. S. A. E. B. T. I. S. O. I. T. A. N. W. A. E. A. M. O. K., & cells., S. S. O. K. P. A. G. L. T. E. O. T. F. H. P. A. N. O. S. H. E. I. I. K. T. A. T. V. M. H. I. T. K. A. A. W. A. I. I. P.-I. M. A. I. (2020) · Plastic and Aesthetic Research · doi:10.20517/2347-9264.2020.150 · Cited by 49
“[82] showed reduced collagen density in wounds from macrophage-depleted mice and Lucas et al.[83] showed that depletion of macrophages at early stages of wound healing reduced the amount of granulation tissue and the size of scars that formed.”
BackgroundRole of collagen XII in skin homeostasis and repair.
Schönborn, K., Willenborg, S., Schulz, J.-N., Imhof, T., Eming, S., Quondamatteo, F., Brinckmann, J., Niehoff, A., Paulsson, M., Koch, M., et al. (2020) · Matrix Biology · doi:10.1016/j.matbio.2020.08.002 · Cited by 57
Self-citationJoshi, N., Pohlmeier, L. M., Greenwald, M. B., Haertel, E., Hiebert, P., Köpf, M., & Werner, S. (2020) · European Journal of Immunology · doi:10.1002/eji.201948438 · Cited by 60
Qin, S., Zheng, J., Xia, Z., Qian, J., Deng, C.-L., & Yang, S. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.01.055 · Cited by 59
Macrophage ferroportin is essential for stromal cell proliferation in wound healing
Recalcati, S., Gammella, E., Buratti, P., Doni, A., Anselmo, A., Locati, M., & Cairo, G. (2018) · Haematologica · doi:10.3324/haematol.2018.197517 · Cited by 68
“lution of inflammation and tissue repair, alternatively polarized M2 macrophages oriented to tissue repair and remodeling, predominate.(1,9) This M1 to M2 switch is required for normal healing.”
BackgroundI-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis
von Moltke, J., & Locksley, R. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.09.009 · Cited by 57
Theocharidis, G., Rahmani, S., Lee, S.-M., Li, Z., Lobao, A., Kounas, K., Katopodi, X.-L., Wang, P., Moon, S., Vlachos, I. S., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121692 · Cited by 66
Macrophage modulation of dental pulp stem cell activity during tertiary dentinogenesis
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IL-17 Promotes Scar Formation by Inducing Macrophage Infiltration
Zhang, J., Qiao, Q., Liu, M., He, T., Shi, J., Bai, X., Zhang, Y., Li, Y., Cai, W., Han, S., et al. (2018) · American Journal Of Pathology · doi:10.1016/j.ajpath.2018.04.005 · Cited by 54
“12 e 14 Depending on the microenvironment, macrophages might polarize to different subtypes, which play different roles in normal and pathologic processes.”
BackgroundHilliard, J. J., Datta, V., Tkaczyk, C., Hamilton, M. M., Sadowska, A., Jones-Nelson, O., O’Day, T. L., Weiss, W. J., Szarka, S., Nguyen, V., et al. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03918-14 · Cited by 57
“Macrophage numbers increase during inflammation and peak during the granulation or proliferation phase of wound healing, and reduced macrophage numbers correlate with delayed wound healing in mice (29).”
BackgroundThe Impact of the Myeloid Response to Radiation Therapy
Gough, M. J., Young, K. H., & Crittenden, M. R. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/281958 · Cited by 57
“These data are closely analogous to those during healing of a skin wound; depletion of macrophages early following injury reduced scar formation and improved healing, while removal during resolution dramatically reduced healing [44].”
ResultRoy, R., Zayas, J. P., Mohamed, M. F., Aboonabi, A., Delgado, K., Wallace, J., Bayat, M., Kuzel, T. M., Reiser, J., & Shafikhani, S. H. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.08.428 · Cited by 59
Therapeutic pro-fibrogenic signaling pathways in fibroblasts
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“major pro-fibrogenic role) as potential pro-fibrotic effectors in other conditions of progressive CID involving lung, kidney, heart and skin [30-33].”
BackgroundIn Vivo Imaging Reveals a Pioneer Wave of Monocyte Recruitment into Mouse Skin Wounds
Rodero, M., Licata, F., Poupel, L., Hamon, P., Khosrotehrani, K., Combadière, C., & Boissonnas, A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108212 · Cited by 55
“Their depletion during the early stage of acute healing severely impairs its speed and quality [3,4,5,6], while their depletion at later stages produces less serious effects, mostly on angiogenesis and fibrosis [5].”
BackgroundYates, C., Bodnar, R., & Wells, A. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0663-0 · Cited by 55
“As neutrophils die, macrophages predominate, accumulating at the wound site following recruitment from circulation and from the resident population [48].”
BackgroundInfluentialArginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing
Szondi, D. C., Wong, J. K. F., Vardy, L. A., & Cruickshank, S. M. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.773866 · Cited by 64
“Inflammatory phase-restricted macrophage depletion led to impaired granulation tissue formation and re-epithelialisation, while the mid proliferative stage-restricted macrophage ablation resulted in severe wound site haemorrhage (Lucas et al., 2010).”
BackgroundColonic epithelial response to injury requires Myd88 signaling in myeloid cells
Malvin, N. P., Seno, H., & Stappenbeck, T. S. (2012) · Mucosal Immunology · doi:10.1038/mi.2011.65 · Cited by 49
Luo, G., Zhou, Z., Huang, C., Zhang, P., Sun, N.-Z., Chen, W., Deng, C.-H., Li, X., Wu, P.-F., Tang, J.-Y., et al. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e17909 · Cited by 53
“They respond quickly to pathogens, limit damage, and participate in tissue repair by promoting an anti-inflammatory phenotype [10,11].”
BackgroundNovel ray of hope for diabetic wound healing: Hydrogen sulfide and its releasing agents
Shi, X.-Y., Li, H.-N., Guo, F., Li, D.-H., & Xu, F. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.05.009 · Cited by 53
“Monocytes-macrophages, macrophage phenotypic transition and reduced phagocytic ability play critical roles in anti-inflammatory, tissue debridement, and cell regulatory functions [54,55].”
BackgroundLiu, C., Xu, Y., Lu, Y., Du, P., Li, X., Wang, C., Guo, P., Diao, L., & Lu, G. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02934-9 · Cited by 59
“In addition, during the proliferative phases, they also promote the reconstitution of vascular networks, facilitate collagen synthesis in the wound bed, and eventually form granulation tissue, providing a temporary matrix for cells to support migration, communication, and proliferation [37, 38].”
BackgroundInteraction of endothelial cells with macrophages—linking molecular and metabolic signaling
Kalucka, J. M., Bierhansl, L., Wielockx, B., Carmeliet, P., & Eelen, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1946-6 · Cited by 57
“Moreover, the role of macrophage-secreted VEGF-A has been shown to be critical for new vessel formation during the processes of tissue repair in a model of skin wound healing [47, 91].”
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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