The DOI matches its Crossref record; 103 of the 105 references it cites were found in a registry or an index; 1 of the 81 sources its claims cite were checked for support.
Immunology of Wound Healing
Open accessAbstract
PURPOSE OF REVIEW: Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal. RECENT FINDINGS: Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation. SUMMARY: Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds.
Overview
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Written from the paper’s full text.
TL;DR
This review summarizes immune mechanisms across hemostasis, inflammation, proliferation, and remodeling, arguing that the critical transition from the inflammatory to the proliferative phase often fails in chronic wounds. It highlights neutrophil apoptosis/efferocytosis and macrophage polarization as key drivers of repair.
Key findings
- Chronic wounds in the USA afflict approximately 6.5 million individuals and cost the healthcare system over 25 billion dollars annually; their mortality effect has been reported as comparable to cancer.
- Normal wound healing is divided into hemostasis (minutes to hours), inflammation (days 1–3), proliferation and repair (days 4–21), and remodeling (days 21–365); the key inflammatory-to-proliferative transition occurs around days 2–5 and often fails in chronic wounds.
- Neutrophils are early responders recruited by IL-8/CXCL8; their apoptosis and macrophage engulfment (efferocytosis) signal a shift to anti-inflammatory, pro-repair macrophages. Persistent neutrophils, NETs, proteases/MMPs, reactive oxygen species, and elevated CXCL8 contribute to chronic, non-healing wounds.
- Anti-inflammatory macrophages promote angiogenesis, granulation tissue, and re-epithelialization via VEGF, TGF-β, PDGF, EGF, KGF, and other signals; impaired pro- to anti-inflammatory macrophage transition—seen with iron overload, hyperglycemia, and hypoxia—stalls healing. Mature scars regain only 80% of initial tensile strength.
Methods
- Narrative review of the literature; no primary data, sample, or statistical analysis are reported.
- Synthesizes immune cell and signaling pathways across the four phases of wound healing, focusing on the inflammatory-to-proliferative transition and chronic wounds.
- Draws on cited animal models, in vitro studies, and human wound observations; no systematic search or meta-analysis is described.
Limitations
- The paper states no limitations.
- Evident from the text: it is a narrative review without systematic search, inclusion criteria, or quality appraisal.
- Evident from the text: many mechanistic conclusions rely on mouse models and in vitro findings, with limited direct human chronic wound data; no original experiments or quantitative synthesis are presented.
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Claims the paper makes
51 Not checked yet · 8 Own interpretation · 6 No basis given · 1 Partly supported · accuracy not yet measured
In the paper
“In impaired models of wound healing, such as diabetes, where infection risk is higher, neutrophils are clearly required [28].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [28] Wilgus TA, Roy S, McDaniel JC. Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care. 2013;2(7):379–88. https://doi.org/10.1089/wound.2012.0383 . source
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
In the paper
“Their influx is mediated by a number of chemical signals, including IL-8, or CXCL8, as mentioned above, and neutrophils have over 30 different receptors that mitigate their migration and activation response [24].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [24] Futosi K, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol. 2013;17(3):638–50. https://doi.org/10.1016/j.intimp.2013.06.034 . source
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In the paper
“normal wound healing can generally be broken down into four over-lapping but distinct steps (Fig. 1). These steps include hemostasis (minutes to hours after injury), inflammation (days 1–3), proliferation and repair (days 4–21), and lastly, wound remodeling (days 21–365) [8, 9].”
§ Immunology of Wound Healing > Introduction
What the sources say
- Not checked yetcites [8] Morton LM, Phillips TJ. Wound healing and treating wounds: differential diagnosis and evaluation of chronic wounds. J Am Acad Dermatol. 2016;74(4):589–605; quiz −6. https://doi.org/10.1016/j.jaad.2015.08.068 . source
- Not checked yetcites [9] Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35–43. https://doi.org/10.1159/000339613 . source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“chronic wounds demonstrate significantly increased levels of the potent neutrophil chemoattractant, CXCL8 [58].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [58] Fivenson DP, Faria DT, Nickoloff BJ, Poverini PJ, Kunkel S, Burdick M, et al. Chemokine and inflammatory cytokine changes during chronic wound healing. Wound Repair Regen. 1997;5(4):310–22. https://doi.org/10.1046/j.1524-475X.1997.50405.x . source
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In the paper
“Platelet activation not only results in hemostasis, but also in the release of growth factors such as platelet-derived growth factor (PDGF) as well as immune mediators that are responsible for activation of the immune system and transition to the inflammatory phase of wound healing.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Hemostasis
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In the paper
“mouse models of wound healing have shown that in non-aged, non-impaired models, neutrophil depletion does not negatively affect wound healing as profoundly as macrophage deletion [25–27].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [25] Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78(1):71–100.
- Not checked yetcites [26] Pinhal-Enfield G, Ramanathan M, Hasko G, Vogel SN, Salzman AL, Boons GJ, et al. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol. 2003;163(2):711–21. https://doi.org/10.1016/s0002-9440(10)63698-x . source
- Not checked yetcites [27] Simpson DM, Ross R. The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest. 1972;51(8):2009–23. https://doi.org/10.1172/jci107007 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“New research has illustrated that chronic wounds fail to shift from the inflammatory to the proliferative phase of wound healing”
§ Immunology of Wound Healing > Introduction
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“recent research has shown that the key transition point lies between the inflammatory and the proliferative phases.”
- Also stated in: § Conclusions · plain
“Recent research has shown that the key transition point in wound healing lies between the inflammatory and the proliferative phases.”
§ Immunology of Wound Healing > Abstract > Summary
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- Also stated in: § Conclusions · plain
None of the sources cited for this claim have been checked yet.
In the paper
“the immune system has been found to play a substantial role due to its impact on several repair mechanisms [6, 7].”
§ Immunology of Wound Healing > Introduction
What the sources say
- Not checked yetcites [6] MA S, MJ N. The innate immune system in acute and chronic wounds. Adv Wound Care. 2016;5(2):65–78. https://doi.org/10.1089/wound.2014.0608 . source
- Not checked yetcites [7] Strbo N, Yin N, Stojadinovic O. Innate and adaptive immune responses in wound epithelialization. Adv Wound Care. 2014;3(7):492–501. https://doi.org/10.1089/wound.2012.0435 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar.”
§ Immunology of Wound Healing > Abstract > Recent Findings
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In sum, the sustained and inappropriate presence of neutrophils at the site of injury is a major contributing factor in non-healing wounds.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state”
§ Immunology of Wound Healing > Abstract > Recent Findings
What the sources say
- Not checked yetcites [47] Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101(4):890–8. https://doi.org/10.1172/jci1112 . source
- Not checked yetcites [48] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61. https://doi.org/10.1038/nri2294 . source
- Not checked yetcites [49] Widgerow AD. Cellular resolution of inflammation—catabasis. Wound Repair Regen. 2012;20(1):2–7. https://doi.org/10.1111/j.1524-475X.2011.00754.x . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases.”
§ Immunology of Wound Healing > Abstract > Summary
What the sources say
- Not checked yetcites [10••]
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“their persistence, as will be discussed in detail below, has been associated with delayed wound healing and chronic wounds.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Unchecked inflammation at this stage can result in abnormal scar formation.”
§ Immunology of Wound Healing > Abstract > Recent Findings
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In physiologic wound repair, neutrophils undergo apoptosis after carrying out their various functions at the site of injury. Local macrophage uptake of apoptotic neutrophils then triggers a transition out of inflammatory phase [47–49].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [47] Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101(4):890–8. https://doi.org/10.1172/jci1112 . source
- Not checked yetcites [48] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61. https://doi.org/10.1038/nri2294 . source
- Not checked yetcites [49] Widgerow AD. Cellular resolution of inflammation—catabasis. Wound Repair Regen. 2012;20(1):2–7. https://doi.org/10.1111/j.1524-475X.2011.00754.x . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The initial events following injury are designed to achieve hemostasis within the first minutes to hours of injury based on a series of serine protease events designed to prevent blood loss [11].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Hemostasis
What the sources say
- Not checked yetcites [11] Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326–36. https://doi.org/10.3109/10409238.2015.1050550 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“More recent evidence indicates that neutrophils can also eliminate organisms residing in the extracellular environment through the deployment of neutrophil extracellular traps (NETs).”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [41] Papayannopoulos V, Zychlinsky A. NETs: a new strategy for using old weapons. Trends Immunol. 2009;30(11):513–21. https://doi.org/10.1016/j.it.2009.07.011 . source
- Not checked yetcites [42] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. https://doi.org/10.1126/science.1092385 . source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“neutrophils defend against wound infection by phagocytosing pathogens then killing them through release of reactive oxygen species, proteases, or antimicrobial proteins [28].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [28] Wilgus TA, Roy S, McDaniel JC. Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care. 2013;2(7):379–88. https://doi.org/10.1089/wound.2012.0383 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Many studies suggest that the prolonged presence of neutrophils and their associated inflammatory mediators in the wound milieu contributes to the formation and persistence of chronic wounds.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [94] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017;25(2):177–91. https://doi.org/10.1111/wrr.12516 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“in a mouse model of iron overload, local wound macrophages persisted in a pro-inflammatory state with excess production of inducible nitric oxide synthase (iNOS), IL-12, and TNF-α, in addition to free radicals, leading to impaired wound healing [81].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [81] Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Investig. 2011;121(3):985–97. https://doi.org/10.1172/jci44490 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent evidence indicates that myofibroblast-induced fibrosis can be over-activated, not only in the setting of signaling through TGF-β, but also in the setting of Th2-derived cytokines IL-4 and IL-13; Th1 cytokines, such as IFN-γ, attenuate excessive scar formation [100, 101].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [100] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. https://doi.org/10.1038/nri1412 . source
- Not checked yetcites [101] Hinz B. The role of myofibroblasts in wound healing. Curr Res Transl Med. 2016;64(4):171–7. https://doi.org/10.1016/j.retram.2016.09.003 . source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent evidence indicates that myofibroblast-induced fibrosis can be over-activated, not only in the setting of signaling through TGF-β, but also in the setting of Th2-derived cytokines IL-4 and IL-13; Th1 cytokines, such as IFN-γ, attenuate excessive scar formation [100, 101].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [100] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. https://doi.org/10.1038/nri1412 . source
- Not checked yetcites [101] Hinz B. The role of myofibroblasts in wound healing. Curr Res Transl Med. 2016;64(4):171–7. https://doi.org/10.1016/j.retram.2016.09.003 . source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to contraction of wound beds and generation of collagen, myofibroblasts contribute to remodeling by release of MMPs that degrade collagen laid down during granulation tissue formation [96, 97].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [96] Darby IA, Laverdet B, Bonte F, Desmouliere A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301–11. https://doi.org/10.2147/ccid.s50046 . source
- Not checked yetcites [97] Van De Water L, Varney S, Tomasek JJ. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: opportunities for new therapeutic intervention. Adv Wound Care. 2013;2(4):122–41. https://doi.org/10.1089/wound.2012.0393 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [94] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017;25(2):177–91. https://doi.org/10.1111/wrr.12516 . source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Myofibroblasts express smooth muscle actin (SMA), which is responsible for generating the contractile force attributed to this cell type [94, 95].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [94] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017;25(2):177–91. https://doi.org/10.1111/wrr.12516 . source
- Not checked yetcites [95] Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–55. https://doi.org/10.1016/j.ajpath.2012.02.004 . source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This process is dependent upon neogenic hair follicles, which lead to bone morphogenic protein (BMP) signaling and activation of adipocyte transcription factors [98••].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites 98••
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hypertrophic scars arise within 1–2 months of injury, and tend to arise in areas of high tension.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [99] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1–2):113–25. https://doi.org/10.2119/molmed.2009.00153 . source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Normally, myofibroblasts carefully coordinate the breakdown of granulation tissue and replacement with long-lasting type I collagen [100].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [100] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. https://doi.org/10.1038/nri1412 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells such as platelets, fibroblasts, and myofibroblasts.”
§ Immunology of Wound Healing > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Macrophages in the wound site are responsible for phagocytosis of apoptotic neutrophils, a process known as efferocytosis [73••]. This action itself induces macrophages to transition from a pro-inflammatory phenotype, to an anti-inflammatory phenotype”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [73••]
- Not checked yetcites [47] Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101(4):890–8. https://doi.org/10.1172/jci1112 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Keloid scars can occur at any point post-injury, do not tend to occur in areas of high tension, and may grow beyond the borders of the initial scar [99].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [99] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1–2):113–25. https://doi.org/10.2119/molmed.2009.00153 . source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in macrophage-deficient models, angiogenesis is impaired [85].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [85] Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116(5):829–40. https://doi.org/10.1182/blood-2009-12-257832 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
None of the sources cited for this claim have been checked yet.
In the paper
“Macrophages from patients with chronic, non-healing, wounds have been shown to have higher levels of iron, based on Prussian blue staining [82, 83].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [82] Zamboni P, Izzo M, Tognazzo S, Carandina S, De Palma M, Catozzi L, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med. 2006;40(10):1869–73. https://doi.org/10.1016/j.freeradbiomed.2006.01.026 . source
- Not checked yetcites [83] Zamboni P, Tognazzo S, Izzo M, Pancaldi F, Scapoli GL, Liboni A, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg. 2005;42(2):309–14. https://doi.org/10.1016/j.jvs.2005.04.003 . source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“DAMPs and PAMPs (released from necrotic tissue and pathogens, respectively), as well as interferon-γ [(IFN-γ), released from natural killer cells] polarize macrophages into a pro-inflammatory phenotype [64].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [64] Adams DO. Molecular interactions in macrophage activation. Immunol Today. 1989;10(2):33–5. https://doi.org/10.1016/0167-5699(89)90298-3 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Transitioning from a pro-inflammatory macrophage-dominant wound to an anti-inflammatory macrophage-dominant milieu is essential in resolving inflammation and preparing the wound for effective repair [72].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [72] Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69. https://doi.org/10.1038/nri2448 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Certain signals are known to prolong the presence of pro-inflammatory macrophages, including iron overload, which is commonly seen in the skin in the setting of venous stasis [81, 82].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [81] Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Investig. 2011;121(3):985–97. https://doi.org/10.1172/jci44490 . source
- Not checked yetcites [82] Zamboni P, Izzo M, Tognazzo S, Carandina S, De Palma M, Catozzi L, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med. 2006;40(10):1869–73. https://doi.org/10.1016/j.freeradbiomed.2006.01.026 . source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, exciting new research indicates that these wound bed myofibroblasts may further differentiate into fat cells, replenishing subcutaneous adipose tissue.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites 98••
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Myofibroblasts express smooth muscle actin (SMA), which is responsible for generating the contractile force attributed to this cell type [94, 95].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [94] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017;25(2):177–91. https://doi.org/10.1111/wrr.12516 . source
- Not checked yetcites [95] Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–55. https://doi.org/10.1016/j.ajpath.2012.02.004 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Each cell type contributes proteins and molecular signals that transition the cycle through the normal phases of wound healing, including the hemostasis, inflammatory, proliferative, and remodeling phases.”
§ Immunology of Wound Healing > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This remodeling phase is largely driven by myofibroblasts, which develop from fibroblasts in response to both mechanical tension and TGF-β signaling and are responsible for contraction of the wound [94].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [94] Yannas IV, Tzeranis DS, So PTC. Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation. Wound Repair Regen. 2017;25(2):177–91. https://doi.org/10.1111/wrr.12516 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A role for these therapies in cutaneous fibrosis remains to be explored, though in vitro studies have shown that blocking signaling of the related cytokine IL-10 in fibroblasts may decrease keloid scar formation [102].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [102] Shi J, Li J, Guan H, Cai W, Bai X, Fang X, et al. Anti-fibrotic actions of interleukin-10 against hypertrophic scarring by activation of PI3K/AKT and STAT3 signaling pathways in scar-forming fibroblasts. PLoS One. 2014;9(5):e98228. https://doi.org/10.1371/journal.pone.0098228 . source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“New blood vessel formation, referred to as angiogenesis, occurs in a two-step process: vessel sprouting, followed by vessel anastomosis [85].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [85] Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116(5):829–40. https://doi.org/10.1182/blood-2009-12-257832 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Keratinocytes themselves further activate fibroblasts in a feedback loop through the production of fibronectin, tenascin C, and laminin 332 (Fig. 2) [93].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [93] Iorio V, Troughton LD, Hamill KJ. Laminins: roles and utility in wound repair. Adv Wound Care. 2015;4(4):250–63. https://doi.org/10.1089/wound.2014.0533 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Re-epithelialization is initiated by epidermal growth factor (EGF), keratinocyte growth factor (KGF), and transforming growth factor-α (TGF-α), which are produced by platelets, keratinocytes, and activated pro-repair, anti-inflammatory macrophages [92].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [92] Schultz G, Rotatori DS, Clark W. EGF and TGF-alpha in wound healing and repair. J Cell Biochem. 1991;45(4):346–52. https://doi.org/10.1002/jcb.240450407 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Hypertrophic scars arise within 1–2 months of injury, and tend to arise in areas of high tension.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [99] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1–2):113–25. https://doi.org/10.2119/molmed.2009.00153 . source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Keloid scars can occur at any point post-injury, do not tend to occur in areas of high tension, and may grow beyond the borders of the initial scar [99].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [99] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1–2):113–25. https://doi.org/10.2119/molmed.2009.00153 . source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent evidence indicates that myofibroblast-induced fibrosis can be over-activated, not only in the setting of signaling through TGF-β, but also in the setting of Th2-derived cytokines IL-4 and IL-13; Th1 cytokines, such as IFN-γ, attenuate excessive scar formation [100, 101].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [100] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–94. https://doi.org/10.1038/nri1412 . source
- Not checked yetcites [101] Hinz B. The role of myofibroblasts in wound healing. Curr Res Transl Med. 2016;64(4):171–7. https://doi.org/10.1016/j.retram.2016.09.003 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Keloid scars can occur at any point post-injury, do not tend to occur in areas of high tension, and may grow beyond the borders of the initial scar [99].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Repair/Remodeling
What the sources say
- Not checked yetcites [99] Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1–2):113–25. https://doi.org/10.2119/molmed.2009.00153 . source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Alteration of normal signals at any stage can result in impaired wound healing, with non-healing wounds or excessive scar formation, at great cost to both patients and the healthcare system.”
§ Immunology of Wound Healing > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 15
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The inflammatory phase overlaps considerably with initial hemostasis, occurring during the first 72 h after tissue injury [16].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Partly supportedcites [16] Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6. https://doi.org/10.1126/scitranslmed.3009337 . sourceExperimental — accuracy not yet measured
The ‘Inflammatory response’ section says that acute wound-healing phases largely overlap and that the early inflammatory response occurs in parallel with hemostasis. It does not specify that the inflammatory phase occurs during the first 72 hours after injury; searches for that timing found no supporting passage in our copy. Page numbers were unavailable. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
In the paper
“Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8.”
§ Immunology of Wound Healing > Abstract > Recent Findings
What the sources say
- Not checked yetcites [31] Baggiolini M, Loetscher P, Moser B. Interleukin-8 and the chemokine family. Int J Immunopharmacol. 1995;17(2):103–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neutrophils represent the most abundant inflammatory cells to infiltrate a new wound and function mainly to remove debris and prevent infection [22, 23].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [22] Engelhardt E, Toksoy A, Goebeler M, Debus S, Brocker EB, Gillitzer R. Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol. 1998;153(6):1849–60. source
- Not checked yetcites [23] de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016;16(6):378–91. https://doi.org/10.1038/nri.2016.49 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“NETs have also been detected in excess in diabetic foot wounds and have been shown to delay healing, and inhibition of NETosis and NET function in mouse models of delayed wound healing improves outcomes [59•].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [59•]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
None of the sources cited for this claim have been checked yet.
In the paper
“Macrophages play a critical role in wound healing, and their roles in angiogenesis, fibroplasia, cell proliferation, and transition out of the inflammatory phase is clear (Fig. 2) [25–27, 60].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [25] Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78(1):71–100.
- Not checked yetcites [26] Pinhal-Enfield G, Ramanathan M, Hasko G, Vogel SN, Salzman AL, Boons GJ, et al. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol. 2003;163(2):711–21. https://doi.org/10.1016/s0002-9440(10)63698-x . source
- Not checked yetcites [27] Simpson DM, Ross R. The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest. 1972;51(8):2009–23. https://doi.org/10.1172/jci107007 . source
- Not checked yetcites [60] Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23. https://doi.org/10.1017/s1462399411001943 . source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“After hemostasis is achieved, histamine released by the activated complement cascade causes capillary dilation and leakage, accelerating migration of inflammatory cells into the wound bed and full transition to the inflammatory phase of wound healing [15].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Hemostasis
What the sources say
- Not checked yetcites [15] Sinno H, Prakash S. Complements and the wound healing cascade: an updated review. Plast Surg Int. 2013;2013:146764–7. https://doi.org/10.1155/2013/146764 . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“neutrophil-derived proteases, such as elastase and matrix metalloproteinases (MMPs), can degrade healthy extracellular matrix (ECM), and increased levels of these proteases have been repeatedly detected in chronic wounds [52–56].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [52] Briggaman RA, Schechter NM, Fraki J, Lazarus GS. Degradation of the epidermal-dermal junction by proteolytic enzymes from human skin and human polymorphonuclear leukocytes. J Exp Med. 1984;160(4):1027–42. source
- Not checked yetcites [53] Grinnell F, Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. J Invest Dermatol. 1996;106(2):335–41. source
- Not checked yetcites [54] Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M. Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest. 1997;77(3):281–8.
- Not checked yetcites [55] Nwomeh BC, Liang HX, Cohen IK, Yager DR. MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. J Surg Res. 1999;81(2):189–95. https://doi.org/10.1006/jsre.1998.5495 . source
- Not checked yetcites [56] Pirila E, Korpi JT, Korkiamaki T, Jahkola T, Gutierrez-Fernandez A, Lopez-Otin C, et al. Collagenase-2 (MMP-8) and matrilysin-2 (MMP-26) expression in human wounds of different etiologies. Wound Repair Regen. 2007;15(1):47–57. https://doi.org/10.1111/j.1524-475X.2006.00184.x . source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Platelet degranulation also leads to the release of inflammatory mediators such as interleukin (IL)-8, or CXCL8 (a potent neutrophil chemoattractant), in addition to IL-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and activates the complement cascade [9, 14].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Hemostasis
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Dysregulation of any of these events can result in delayed wound healing and the potential to form chronic ulcers and/or excessive scarring [10••].”
§ Immunology of Wound Healing > Introduction
What the sources say
- Not checked yetcites [10••]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Not only do anti-inflammatory, pro-repair macrophages produce VEGF, which promotes vessel sprouting, they also express two transmembrane proteins that have been shown to promote vascular anastomosis [80, 85, 86].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [80] Brancato SK, Albina JE. Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol. 2011;178(1):19–25. https://doi.org/10.1016/j.ajpath.2010.08.003 . source
- Not checked yetcites [85] Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116(5):829–40. https://doi.org/10.1182/blood-2009-12-257832 . source
- Not checked yetcites [86] Affolter M, Zeller R, Caussinus E. Tissue remodelling through branching morphogenesis. Nat Rev Mol Cell Biol. 2009;10:831–42. https://doi.org/10.1038/nrm2797 . source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Wounds without IL-6 lack an appropriate inflammatory response and demonstrate stunted angiogenesis, collagen accumulation, and re-epithelialization [89].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Proliferation
What the sources say
- Not checked yetcites [89] Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N. Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol. 2003;73(6):713–21. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“When the transition from a pro- to an anti-inflammatory macrophage phenotype is impaired, wound healing stalls in the inflammatory phase and a chronic wound results [10••].”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
What the sources say
- Not checked yetcites [10••]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Additional signals, such as hyperglycemia in the setting of diabetes, hypoxia in the setting of arterial or venous insufficiency, or secondary infection likely also contribute to the persistence of pro-inflammatory macrophages.”
§ Immunology of Wound Healing > Four Stages of Wound Healing > Inflammation
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If wounds fail to transition from the inflammatory phase, pro-inflammatory macrophages persist and non-healing wounds develop.”
§ Immunology of Wound Healing > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Numerous signals are responsible for the transition, most notably the apoptosis and phagocytosis of wound-bed resident neutrophils (efferocytosis).”
§ Immunology of Wound Healing > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
The paper relies on this without support.
Findings from mouse models of wound healing can be generalized to human wound healing and chronic wounds.
“mouse models of wound healing have shown that in non-aged, non-impaired models, neutrophil depletion does not negatively affect wound healing as profoundly as macrophage deletion [25–27].”
“in a mouse model of iron overload, local wound macrophages persisted in a pro-inflammatory state with excess production of inducible nitric oxide synthase (iNOS), IL-12, and TNF-α, in addition to free radicals, leading to impaired wound healing [81].”
“inhibition of NETosis and NET function in mouse models of delayed wound healing improves outcomes [59•].”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Immune regulators promote better surveillance and wound clearance in multiple tissues [75, 76].”
From Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin (2020) · cites this paper as [75]
Experimental — accuracy not yet measuredIn the citing paper
“Indeed, these cells are known to be irreplaceable partners in a successful wound healing70.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [70]
In the citing paper
“The absence or over-abundance of any of these cell types would derail the normal healing process, leading healing astray and causing pathological healing such as fibrosis70.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [70]
Citations
Cites
Neutrophil Extracellular Traps Kill Bacteria
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., Weinrauch, Y., & Zychlinsky, A. (2004) · Science · doi:10.1126/science.1092385 · Cited by 10,268
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
Pattern Recognition Receptors and Inflammation
Takeuchi, O., & Akira, S. (2010) · Cell · doi:10.1016/j.cell.2010.01.022 · Cited by 8,895
Mizgerd, J. P., Kubo, H., Kutkoski, G. J., Bhagwan, S. D., Scharffetter-Kochanek, K., Beaudet, A. L., & Doerschuk, C. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.8.1357 · Cited by 7,332
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335
MANTOVANI, A., SOZZANI, S., LOCATI, M., ALLAVENA, P., & SICA, A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02302-5 · Cited by 5,528
Neutrophil recruitment and function in health and inflammation
Kolaczkowska, E., & Kubes, P. (2013) · Nature Reviews Immunology · doi:10.1038/nri3399 · Cited by 5,472
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190
Wound repair and regeneration: Mechanisms, signaling, and translation
Eming, S. A., Martin, P., & Tomic-Canic, M. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009337 · Cited by 3,562
Cited by
Sorted by citations
Immunology of Acute and Chronic Wound Healing
Raziyeva, K., Kim, Y., Zharkinbekov, Z., Kassymbek, K., Jimi, S., & Saparov, A. (2021) · Biomolecules · doi:10.3390/biom11050700 · Cited by 1,152
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
Rational Design of Immunomodulatory Hydrogels for Chronic Wound Healing
Kharaziha, M., Baidya, A., & Annabi, N. (2021) · Advanced Materials · doi:10.1002/adma.202100176 · Cited by 735
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
“Once initiated, the remodeling phase can continue for at least one year post-injury [81,366].”
BackgroundChouhan, D., Dey, N., Bhardwaj, N., & Mandal, B. B. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119267 · Cited by 537
Metadata
- Authors
- Ellis, S., Lin, E. J., & Tartar, D.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Tartar, Danielle
- ORCID
- Tartar, Danielle
- Venue
- Current Dermatology Reports
- Published
- 2018-09-28
- Volume
- 7
- Issue
- 4
- Pages
- 350-358
- ISSN
- 2162-4933 (ISSN-L)
- PMC
- PMC6244748
- OpenAlex
- W2892642834
- Semantic Scholar
- 2db5782e12aeaff45400ab4236b744f21a3178e0
- Cited by
- 625
- References
- 105
- Citations by year
- 2026: 65 · 2025: 114 · 2024: 109 · 2023: 90 · 2022: 96 · 2021: 86 · 2020: 44 · 2019: 21
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Current Dermatology Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- wound healing, chronic wounds, skin wound healing, neutrophils, efferocytosis, macrophages, interleukin-8, inflammation, angiogenesis, granulation tissue, myofibroblasts, scar formation, keratinocytes, dermal cells, immune signaling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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