The DOI matches its Crossref record; 80 of the 85 references it cites were found in a registry or an index; none of the 60 sources its claims cite is checked for support yet.
Macrophage phenotypes during tissue repair
Open accessAbstract
Review on tissue repair and M1-like to M2a-like macrophages, exhibiting important differences from in vitro phenotypes. Mp are crucial for tissue repair and regeneration but can also contribute to tissue damage and fibrosis. Mp can adopt a variety of functional phenotypes in response to different stimuli; two of the best-characterized in vitro phenotypes are a proinflammatory “M1” phenotype, produced by exposure to IFN-γ and TNF-α, and an anti-inflammatory “M2a” phenotype, produced by IL-4 or IL-13. M2a Mp are frequently termed “wound healing” Mp, as they express factors that are important for tissue repair. This review will summarize current knowledge of Mp phenotypes during tissue repair and will argue that these in vivo Mp populations are heterogeneous and temporally regulated and do not conform to existing, in vitro-defined M1 or M2 phenotypes. Mp during the early stages of tissue repair exhibit a more proinflammatory phenotype than their later counterparts, which in turn may exhibit some M2a-associated characteristics. However, phenotypic markers that appear to be coregulated in cultured Mp can be expressed independently of each other in vivo. Additionally, M1- and M2-associated markers may be expressed simultaneously by actual tissue-repair Mp. Improved understanding of Mp phenotypes and their regulation may assist in generation of novel therapies based on manipulating Mp function to improve healing.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that macrophages present during in vivo tissue repair are heterogeneous and temporally regulated and do not conform to the in vitro-defined M1 or M2a phenotypes. Early-repair macrophages are more proinflammatory than later ones, but neither population matches a discrete cultured phenotype.
Key findings
- M2a macrophages are widely termed "wound-healing" macrophages because IL-4/IL-13 treatment up-regulates TGF-β, arginase, and ECM components, but the review argues this nomination is "an oversimplification at best and likely not warranted."
- In a mouse sponge-implantation wound model, macrophages produced TGF-β despite no detectable IL-4 or IL-13 in wound fluids or cells and no Stat6 phosphorylation, indicating M2a activation is sufficient but not necessary for TGF-β production.
- M2a-associated markers are regulated independently in vivo: in murine subcutaneous wounds, CD206 increased with time, Ym1 was highest at 1 day and then decreased, and dectin-1 remained constant; CD206 expression was similar among TNF-α-high, -low, or -negative macrophages.
- iNOS expression by tissue-repair macrophages is context-dependent: highest at 1 day in mouse kidney ischemia-reperfusion, but only 10–15% of wound macrophages were iNOS-positive at peak in rat excisional skin wounds, and mouse muscle macrophages expressed iNOS after chemical injury but not after laceration.
- Human M2a macrophages or monocytes do not express arginase (unlike rodent), and human iNOS activity is much lower or absent (~20 nmol nitrite/10⁶ cells/24 h in rodent M1 macrophages; often undetectable in human).
Methods
- Narrative review summarizing current knowledge of macrophage phenotypes during tissue repair, drawing on cited in vitro and in vivo studies across skin, skeletal muscle, liver, kidney, and peritoneum.
- Compares in vitro-defined M1/M2a/b/c phenotypes with in vivo tissue-repair macrophage populations, including a summary table (Table 1) of activators, cytokines, iNOS, and markers (CD206, dectin-1, Ym1) across early and late repair.
- Includes some unpublished results from the authors' laboratory (mouse skeletal muscle laceration and chemical injury models).
Limitations
- Stated: many studies reporting M2a markers during repair did not verify that markers were expressed by macrophages rather than other cell types; whole-tissue cytokine content cannot determine macrophage phenotype; direct quantitative comparisons of cytokine production between cultured M1/M2a macrophages and in vivo tissue-repair macrophages are currently unavailable.
- Stated: rodent and human macrophages do not exhibit entirely similar responses to in vitro activation, and whether species-dependent differences exist in in vivo repair is undetermined.
- Evident from the text: several key supporting observations are unpublished results from the authors' own laboratory, and the review notes that the factors regulating in vivo macrophage phenotype "remain to be elucidated."
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Claims the paper makes
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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
“Mp can adopt a variety of functional phenotypes in response to different stimuli; two of the best-characterized in vitro phenotypes are a proinflammatory”
§ Macrophage phenotypes during tissue repair > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Mp, in particular, are known to be essential to regeneration, repair, and remodeling in numerous tissues [1][2][3][4][5].”
§ Macrophage phenotypes during tissue repair > Introduction
What the sources say
- Not checked yetcites [1][2][3][4][5]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“However, chronic inflammation and persistent Mp accumulation are often associated with tissue destruction and fibrosis [6 -8].”
§ Macrophage phenotypes during tissue repair > Introduction
What the sources say
- Not checked yetcites [6] Moreira, 2011, Macrophages in allergic asthma: fine-tuning their pro- and anti-inflammatory actions for disease resolution, J. Interfron Cytokine Res. source
- Not checked yetcites [7] Moyer, 2011, Regeneration versus fibrosis in skeletal muscle, Curr. Opin. Rheumatol. source
- Not checked yetcites [8] Murray, 2011, Protective and pathogenic functions of macrophage subsets, Nat. Rev. Immunol. source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“The M1-associated cytokines IL-1, TNF-␣, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin [33,60,61], liver [62], kidney [63], and skeletal muscle [57,64].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
- Not checked yetcites [60] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine source
- Not checked yetcites [61] Sindrilaru, 2011, An unrestrained pro-inflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice, J. Clin. Invest. source
- Not checked yetcites [62] Karlmark, 2010, The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes, Hepatology source
- Not checked yetcites [63] Lee, 2011, Distinct macrophage phenotypes contribute to kidney injury and repair, J. Am. Soc. Nephrol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Thus, available evidence indicates that M1 and M2a/b/c are not discrete Mp differentiation states but instead represent convenient but limited and arbitrary in vitro-defined reference points on a time-dependent and multidimensional continuum of possible Mp phenotypes and functions [9].”
§ Macrophage phenotypes during tissue repair > EVOLVING Mp ACTIVATION PARADIGMS
What the sources say
- Not checked yetcites [9] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat. Rev. Immunol. source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Thus, the presence of arginase or even of arginase-expressing Mp does not necessarily imply that IL-4/IL-13-induced M2a Mp are present in a tissue.”
§ Macrophage phenotypes during tissue repair > EVIDENCE FOR M2a Mp AS TISSUE-REPAIR Mp
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In the paper
“Importantly, in contrast to rodent Mp, human M2a Mp or monocytes do not express arginase [36,37].”
§ Macrophage phenotypes during tissue repair > EVIDENCE FOR M2a Mp AS TISSUE-REPAIR Mp
What the sources say
- Not checked yetcites [36] Munder, 2005, Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity, Blood source
- Not checked yetcites [37] Raes, 2005, Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation, J. Leukoc. Biol. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“This review will address recent advances in our understanding of Mp phenotypes during tissue repair and will argue that the Mp populations that participate in tissue repair are not analogous to in vitro M2a Mp.”
§ Macrophage phenotypes during tissue repair > Introduction
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearA 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
“However, phenotypic markers that appear to be coregulated in cultured Mp can be expressed independently of each other in vivo.”
§ Macrophage phenotypes during tissue repair > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearA 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
“Mp during the early stages of tissue repair exhibit a more proinflammatory phenotype than their later counterparts, which in turn may exhibit some M2a-associated characteristics.”
§ Macrophage phenotypes during tissue repair > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
- Probably not a substantial claim. 5
- It may state two separate claims as one. 24
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly, after mouse skeletal muscle laceration, Mp expression of TGF- mRNA and IL-10 mRNA appears to peak early, ϳ3 days postinjury (unpublished results).”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Studies from our own laboratory have produced contradictory data in two different mouse muscle injury models: skeletal muscle Mp express iNOS mRNA at 5 days after chemically induced injury [57] but do not express iNOS at any time-point after laceration injury (unpublished results).”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [57] Cheng, 2008, Endogenous interferon-γ is required for efficient skeletal muscle regeneration, Am. J. Physiol. Cell. Physiol. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“For instance, in a mouse wound-healing model, Mp expression of the M2a marker CD206 does not require IL-4 or IL-13 and does not correlate, negatively or otherwise, with TNF-␣ production [33].”
§ Macrophage phenotypes during tissue repair > EVIDENCE FOR M2a Mp AS TISSUE-REPAIR Mp
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“two of the best-characterized in vitro phenotypes are a proinflammatory”
§ Macrophage phenotypes during tissue repair > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“M2a Mp are frequently termed”
§ Macrophage phenotypes during tissue repair > Abstract
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The M1 activator IFN-␥ is up-regulated rapidly after injury to skeletal muscle and skin and is required for proper healing of these tissues [55][56][57][58].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [55][56][57][58]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Thus, whereas it is clear that treatment of cultured Mp with particular cytokines produces characteristic phenotypes, the presence of one or a few phenotypic markers in vivo does not demonstrate that the Mp was activated by the associated cytokine or that other aspects of the phenotype induced by that cytokine will also be present.”
§ Macrophage phenotypes during tissue repair > EVIDENCE FOR M2a Mp AS TISSUE-REPAIR Mp
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Wound healing is thus not a single, well-defined function of Mp but comprises its own spectrum of overlapping functions, including phagocytosis, secretion of cytokines and growth factors, as well as matrix remodeling, all of which may be performed by Mp of different phenotypes.”
§ Macrophage phenotypes during tissue repair > EVOLVING Mp ACTIVATION PARADIGMS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“In numerous physiological and pathological states, Mp exhibit extensive heterogeneity and plasticity, and tissue repair is no exception.”
§ Macrophage phenotypes during tissue repair > Introduction
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Taken together, existing data on anti-inflammatory cytokine production suggest that Mp may become more M2a-like as repair progresses, although this transition may not happen in all situations.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
In the paper
“In contrast, in a mouse sponge-implantation model of skin wounding, deletion of IL-4R␣ has no effect on Mp phenotype, and IL-4 and IL-13 are not detected in wound cells or fluids at any time, indicating that despite their predominantly anti-inflammatory cytokine profile, these cells are not bona fide M2a Mp [33].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, during mouse skin wound healing, Mp expression of TGF- mRNA and protein increases over the first 7-10 days postinjury, whereas proinflammatory cytokine production decreases [33,60], consistent with the expression of an M2a-like phenotype during the later stages of repair.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Similarly, after peritoneal incisional wounding, peritoneal exudate cells transiently express elevated Ym1 and FIZZ1 mRNA, although this cell population contains lymphocytes and neutrophils in addition to Mp [70], and each of these cell types could express one or both genes [76,77].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [70] Loke, 2007, Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection, J. Immunol. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Seven days after photochemical injury to the liver, CD206ϩ cells are observed near the border of the injured site [68], although these cells were not verified specifically as Mp, and no other time-points were examined.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [68] Kawao, 2011, Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice, Thromb. Haemost. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Collectively, data from these studies indicate that the M2a markers CD206, Ym1, and dectin-1 can be regulated independently of each other in skin-wound Mp and can be coexpressed with M1-associated or proinflammatory genes and proteins.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In murine skeletal muscle, however, Mp expression of TGF- and IL-10 mRNA increases over the first few days after toxin-induced injury, peaks during the intermediate stages of healing, and then declines sharply, despite continued presence of Mp within the healing muscle [65].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [65] Perdiguero, 2011, p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair, J. Cell Biol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Thus, Mp during skin wound healing exhibit a heterogeneous and temporally regulated phenotype that does not conform strictly to M1/M2 categorization [33].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Tissue repair in mice is representative of tissue repair in humans.
- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
In the paper
“However, although CD206, Ym1, and dectin-1 are expressed by murine subcutaneous wound Mp at 1, 3, and 7 days postinjury [33], these three M2a-associated proteins exhibit entirely different temporal patterns: CD206 increases somewhat with time, whereas Ym1 is expressed most highly at 1-day postinjury and then decreases, and dectin-1 expression remains constant [33].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 studies in other tissues have reported that M2a markers are present during tissue repair, but many of these studies have not determined whether these markers are expressed by Mp or by other cell types, and any conclusions drawn regarding Mp phenotype are therefore dubious.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition to proinflammatory cytokine production, robust expression of iNOS is a hallmark of M1 activation in rodent Mp [14], although iNOS activity in human Mp appears to be much lower or absent entirely (ϳ20 nmol nitrite/10 6 cells/24 h in rodent M1 Mp; often undetectable in human Mp) [66].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Additionally, as IL-4/-13 activation is not always required for up-regulation of IL-10 and TGF- [33], the presence of other aspects of the M2a phenotype should not be inferred from cytokine expression alone.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, IL-4 gene expression is elevated from 1 to 7 days in rat skin wounds [56], and protein expression is elevated between 12 h and 10 days in human skin wounds (peak ϳ12 pg/mg protein in injured skin vs. nearly undetectable in uninjured) [58]; IL-4 protein is present at similar levels in infarcted rat myocardium [72].”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
What the sources say
- Not checked yetcites [56] Miao, 2012, Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation, Wound Repair Regen. source
- Not checked yetcites [58] Takamiya, 2008, Simultaneous detection of eight cytokines in human dermal wounds with a multiplex bead-based immunoassay for wound age estimation, Int. J. Legal Med. source
- Not checked yetcites [72] Fraccarollo, 2008, Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response, Hypertension source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“In short, tissuerepair Mp exhibit complex and heterogeneous phenotypes that change throughout the repair process and do not correspond to existing, in vitro -defined categories.”
§ Macrophage phenotypes during tissue repair > CONCLUDING REMARKS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Whereas Mp are known to promote tissue-repair functions such as wound debridement, cell proliferation, angiogenesis, and matrix remodeling, much remains to be learned about the mechanisms by which Mp accomplish these functions.”
§ Macrophage phenotypes during tissue repair > CONCLUDING REMARKS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no 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
“A proinflammatory-to-anti-inflammatory transition may indeed occur in many situations, although this appears to be context-dependent”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Whereas Mp during the early stages of tissue repair seem to present a more generally proinflammatory profile than their later counterparts, early Mp may lack iNOS expression or may express CD206, Ym1, and IL-10 in addition to proinflammatory cytokines, indicating that these early-repair Mp do not exhibit an entirely M1 phenotype.”
§ Macrophage phenotypes during tissue repair > CONCLUDING REMARKS
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Given the growing belief that M2a Mp participate in tissue repair, surprisingly few studies have actually examined Mp-specific expression of M2a-associated genes or proteins in vivo or performed quantitative comparisons of cytokine production by cultured M1/M2a Mp versus in vivo tissuerepair Mp.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Similarly, whereas many potential modulators of Mp activation have been identified in vitro, the actual factors that regulate Mp phenotype during tissue repair remain to be elucidated.”
§ Macrophage phenotypes during tissue repair > CONCLUDING REMARKS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Tissue repair in mice is representative of tissue repair in humans.
“In mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair [33,60,61,63].”
The paper relies on this without support.
The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
“Across diverse tissues, repair after injury occurs in overlapping phases of inflammation, proliferation, and remodeling.”
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
“The classical model distinguishes two major polarization phenotypes, which represent a continuum, providing a balance between the pro‐ and anti‐inflammatory responses by alternating between classically (M1) or alternatively (M2) activated macrophages.[ 37 , 38 ]”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“Recent studies have shown that Mp phenotypes change over the different phases of tissue repair and that the sequential appearance of these phenotypes may be required for efficient repair (11,14,29,49,50).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [50]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Table says the IL-10 time course is unknown despite describing it in muscle
MinorTable 1 says the IL-10 time course is not known, but the text describes a rise, intermediate peak, and subsequent decline in macrophage IL-10 mRNA after toxin-induced skeletal muscle injury. If the table means only skin wounds, it does not say so.
“TGF- increases with time (skin); IL-10 time course not known.”
“In murine skeletal muscle, however, Mp expression of TGF- and IL-10 mRNA increases over the first few days after toxin-induced injury, peaks during the intermediate stages of healing, and then declines sharply, despite continued presence of Mp within the healing muscle [65].”
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Items 101–200 of 654
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“These results are in agreement with studies describing the sequential profile of M1 and M2 macrophages in animal and human models of acute wound healing (Deonarine et al., 2007; Troidl et al., 2009; Novak and Koh, 2013).”
BackgroundResultDental implant surface chemistry and energy alter macrophage activation in vitro
Hotchkiss, K. M., Ayad, N. B., Hyzy, S. L., Boyan, B. D., & Olivares‐Navarrete, R. (2016) · Clinical Oral Implants Research · doi:10.1111/clr.12814 · Cited by 106
“The anti-inflammatory M2 response is characterized by high levels of IL-4, IL-10, and transforming growth factor beta-1 (TGFb1) (Gordon & Taylor 2005; Brancato & Albina 2011; Novak & Koh 2013) and more recently expression of genes Ym1 (Chil3) and Fizz1 (Retnla).”
BackgroundLi, L., Li, Q., Gui, L., Deng, Y., Wang, L., Jiao, J., Hu, Y., Lan, X., Hou, J., Li, Y., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.03.037 · Cited by 103
“pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS), which can exacerbate harmful inflammatory responses [22,23].”
BackgroundPathophysiological relevance of macrophage subsets in atherogenesis
Liberale, L., Dallegri, F., Carbone, F., & Montecucco, F. (2016) · Thrombosis and Haemostasis · doi:10.1160/th16-08-0593 · Cited by 103
“Conversely, M2a might promote deposition of extracellular matrix by the release of TGF-β, so that they have been described as “tissue-repairing” macrophages (73, 74) (▶ Table 1).”
BackgroundWang, Y., Chaffee, T. S., LaRue, R. S., Huggins, D. N., Witschen, P. M., Ibrahim, A. M., Nelson, A., Machado, H. L., & Schwertfeger, K. L. (2020) · eLife · doi:10.7554/elife.57438 · Cited by 99
Role of metal oxide nanoparticles in histopathological changes observed in the lung of welders
Andujar, P., Simon-Deckers, A., Galateau-Sallé, F., Barbara Fayard, C., Beaune, G., Clin, B., Billon‐Galland, M., Durupthy, O., Pairon, J. ‐., Doucet, J., et al. (2014) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-11-23 · Cited by 99
“An LPS contamination of our NP could have been responsible for the M1-like phenotype of THP-1 macrophages in vitro [48].”
BackgroundDamanik, F. F. R., Rothuizen, T. C., van Blitterswijk, C., Rotmans, J. I., & Moroni, L. (2014) · Scientific Reports · doi:10.1038/srep06325 · Cited by 97
Ishida, Y., Kimura, A., Nosaka, M., Kuninaka, Y., Hemmi, H., Sasaki, I., Kaisho, T., Mukaida, N., & Kondo, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-17007-8 · Cited by 97
Blocking AGE-RAGE Signaling Improved Functional Disorders of Macrophages in Diabetic Wound
Wang, Q., Zhu, G., Cao, X., Dong, J., Song, F., & Niu, Y. (2017) · Journal of Diabetes Research · doi:10.1155/2017/1428537 · Cited by 98
“Because macrophages involved in diabetic wound healing display a switch disorder between proinflammatory and prohealing phenotypes [10, 22], we examined whether blocking the AGE-RAGE interaction could reverse these defects.”
BackgroundYe, J., Xie, C., Wang, C., Huang, J., Yin, Z., Heng, B. C., Chen, X., & Shen, W. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.04.017 · Cited by 97
“The traditional classification of M1 and M2 is based on in vitro characterization, in which M1 phenotype is stimulated by lipopolysaccharide (LPS), interferon-gamma (IFN-γ) and tumor necrosis factor-α (TNF-α), while M2 phenotype is stimulated by IL10, IL-4 or IL-13 [23,24] (Fig.”
BackgroundInfluentialSeebach, E., Freischmidt, H., Holschbach, J., Fellenberg, J., & Richter, W. (2014) · Acta Biomaterialia · doi:10.1016/j.actbio.2014.07.017 · Cited by 92
Barrett, J. P., Henry, R. J., Villapol, S., Stoica, B. A., Kumar, A., Burns, M. P., Faden, A. I., & Loane, D. J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0843-4 · Cited by 94
“Similar to responses in wound healing macrophages [42], coincident pro- and anti-inflammatory activation may be an attempt to fine-tune the injury response in which the two pathways support each other to facilitate neuroprotection and immune resolution that may be important for neurorestoration after TBI, thereby reve…”
BackgroundBeneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy
Uchida, N., Kushida, Y., Kitada, M., et al. (2017) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016070775 · Cited by 93
Zhu, Y., Yao, Z., Liu, Y., Zhang, W., Geng, L., & Ni, T. (2020) · International Journal of Nanomedicine · doi:10.2147/ijn.s225197 · Cited by 93
Patsalos, A., Halász, L., Medina-Serpas, M. A., Berger, W. K., Dániel, B., Tzerpos, P., Kiss, M., Nagy, G., Fischer, C., Simándi, Z., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20210420 · Cited by 94
“These findings collectively suggest that the successive immune cell states from circulating inflammatory monocytes via inflammatory MFs to repair type MFs can be interpreted as a hierarchical continuum of cell states (Novak and Koh, 2013).”
BackgroundDrosophila as a model to study the role of blood cells in inflammation, innate immunity and cancer
Wang, L., Kounatidis, I., & Ligoxygakis, P. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00113 · Cited by 94
“…as the key player in inflammatory responses which accompany infection, Frontiers in Cellular and Infection Microbiology www.frontiersin.org January 2014 | Volume 3 | Article 113 | 1 CELLULAR AND INFECTION MICROBIOLOGY tissue damage and wound healing (Mantovani et al., 2013; Novak and Koh, 2013).”
Biomaterials-Mediated Regulation of Macrophage Cell Fate
Liu, Y., & Segura, T. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.609297 · Cited by 92
“For example, macrophages in wounds exhibit a complicated phenotype with features found in both M1 and M2 macrophages (Daley et al., 2010; Novak and Koh, 2013).”
BackgroundMacrophage polarity and wound age determination
Kuninaka, Y., Ishida, Y., Ishigami, A., Nosaka, M., Matsuki, J., Yasuda, H., Kofuna, A., Kimura, A., Furukawa, F., & Kondo, T. (2022) · Scientific Reports · doi:10.1038/s41598-022-24577-9 · Cited by 95
Regenerative inflammation: When immune cells help to re‐build tissues
Caballero‐Sánchez, N., Alonso‐Alonso, S., & Nagy, L. (2022) · FEBS Journal · doi:10.1111/febs.16693 · Cited by 100
“There are similarities in the cytokine production of M1 macrophages and the initial pro-inflammatory monocyte-derived macrophages, whereas the repair macrophages are more alike to M2 macrophages [28].”
BackgroundMeng, F. W., Slivka, P. F., Dearth, C. L., & Badylak, S. F. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2014.12.044 · Cited by 87
“roles in tissue remodeling and homeostasis [22].”
Aging, inflammaging and immunosenescence as risk factors of severe COVID-19
Tizazu, A. M., Mengist, H. M., & Demeke, G. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00309-5 · Cited by 96
“Recent findings have showed that the M1/M2 polarization do not fully capture the different phenotypes that exist within the macrophage activation [107].”
BackgroundTan, X., Gao, P., Li, Y., Qi, P., Liu, J., Shen, R., Wang, L., Huang, N., Xiong, K., Tian, W., et al. (2020) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.06.024 · Cited by 91
“Considering vascular stent implantation, M1 macrophages are involved in the early inflammatory response to vascular tissue injury caused by stent implantation, and M2 macrophages are involved in late tissue repair [48].”
BackgroundVariability of Platelet-rich Plasma Preparations
Russell, R. P., Apostolakos, J. M., Hirose, T., et al. (2013) · Sports Medicine and Arthroscopy Review · doi:10.1097/jsa.0000000000000007 · Cited by 87
Macrophage polarization in nerve injury: do Schwann cells play a role?
Stratton, J. A., & Shah, P. T. (2016) · Neural Regeneration Research · doi:10.4103/1673-5374.175042 · Cited by 86
“This observation has also been made in other tissues (Novak and Koh, 2013a, b; Gensel and Zhang, 2015).”
Macrophages in tumor: An inflammatory perspective
Goswami, K. K., Bose, A., & Baral, R. (2021) · Clinical Immunology · doi:10.1016/j.clim.2021.108875 · Cited by 88
Electrospun kaolin-loaded chitosan/PEO nanofibers for rapid hemostasis and accelerated wound healing
Liu, T., Zhang, Z., Liu, J., Dong, P., Tian, F., Li, F., & Meng, X. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.07.186 · Cited by 85
Ulivi, V., Tasso, R., Cancedda, R., & Descalzi, F. (2014) · Stem Cells and Development · doi:10.1089/scd.2013.0567 · Cited by 82
“Macrophages mediate the in-flammation because they maintain a proinflammatory phenotype in order to inhibit possible infections, but they switch to a proresolving phenotype as soon as the initial ‘‘emer-gency’’ is over [31,32].”
Photobiomodulation and different macrophages phenotypes during muscle tissue repair
Souza, N. H. C., Mesquita‐Ferrari, R. A., Rodrigues, M. F. S. D., da Silva, D. D. F. T., Ribeiro, B. G., Alves, A. N., Garcia, M. P., Nunes, F. D., da Silva, E. M., França, C. M., et al. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13757 · Cited by 84
“TNF-α is a proinflammatory cytokine that stimulates myogenic cell proliferation, but also inhibits its differentiation and fusion.(3,24) Therefore, the decrease in TNF-α expression during the experimental periods could explain the decrease in myonecrosis on Day 2 and the increase in immature muscle fibres on Day 7 in…”
BackgroundKim, M. E., Na, J. Y., & Lee, J. S. (2018) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2018.1424902 · Cited by 82
Kohno, H., Maeda, T., Perusek, L., Pearlman, E. M., & Maeda, A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301738 · Cited by 82
“5D), because M1 macrophages contribute to inflammation, whereas M2 macrophages have an anti-inflammatory role (23).”
BackgroundM2 macrophages contribute to osteogenesis and angiogenesis on nanotubular TiO 2 surfaces
Wang, J., Shi, Q., Liu, X., Xu, L., Miao, X., Xu, Z., Cao, L., Wang, H., & Jiang, X. (2017) · Journal of Materials Chemistry B · doi:10.1039/c6tb03364d · Cited by 82
Chen, L., Brar, M. S., Leung, F. C.-C., & Hsiao, W. L. W. (2016) · Oncotarget · doi:10.18632/oncotarget.8886 · Cited by 81
“com/oncotarget into M2 cells, and increase of M2 cells can contribute to an enhanced tissue repair and reduce pathological inflammation [35, 36].”
BackgroundLi, D., Li, Y., Shrestha, A., Wang, S., Wu, Q., Li, L., Guan, C., Wang, C., Fu, T., Liu, W., et al. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201900002 · Cited by 79
Fernandes, K., Souza, N., Mesquita-Ferrari, R., da Silva, D. D. F. T., Rocha, L. A., Alves, A. N., Sousa, K. D. B., Bussadori, S., Hamblin, M. R., & Nunes, F. (2015) · Journal of Photochemistry and Photobiology. B: Biology · doi:10.1016/j.jphotobiol.2015.10.015 · Cited by 80
Regeneration and Repair of Skin Wounds: Various Strategies for Treatment
Rezaie, F., Momeni‐Moghaddam, M., & Naderi‐Meshkin, H. (2019) · The International Journal of Lower Extremity Wounds · doi:10.1177/1534734619859214 · Cited by 80
Falkenham, A., de Antueno, R., Rosin, N. L., Betsch, D. M., Lee, T. D. G., Duncan, R., & Légaré, J. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.11.027 · Cited by 77
Slivka, P. F., Dearth, C. L., Keane, T. J., Meng, F. W., Medberry, C. J., Riggio, R. T., Reing, J. E., & Badylak, S. F. (2014) · Biomaterials Science · doi:10.1039/c4bm00189c · Cited by 77
Xia, Y., He, X., Xu, X., Tian, B., An, Y., & Chen, F. (2020) · PeerJ · doi:10.7717/peerj.8970 · Cited by 80
Anders, C. B., Lawton, T., Smith, H. L., Garret, J., Doucette, M., & Ammons, M. C. B. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.6a1120-744r · Cited by 78
Macrophage Polarization: An Important Candidate Regulator for Lung Diseases
Deng, L., Jian, Z., Xu, T., Li, F., Deng, H., Zhou, Y., Lai, S., Xu, Z., & Zhu, L. (2023) · Molecules · doi:10.3390/molecules28052379 · Cited by 85
“Generally, M2 macrophages highly express CD163, CD206, CD209, scavenger receptor A (SR-A), SR-B1, CCR2, CXCR1, and CXCR2 [29,38].”
Lambert, C., Preijers, F. W. M. B., Demirel, G. Y., & Sack, U. (2015) · Cytometry Part B Clinical Cytometry · doi:10.1002/cyto.b.21280 · Cited by 83
“In this process, they are clearing damaged tissues due to injury, infection, ischemia, regeneration, or graft rejection and participate in their repair or renewal (9,10).”
BackgroundMazur, A., Holthoff, E. R., Vadali, S., Kelly, T. J., & Post, S. R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150287 · Cited by 75
Yin, W., Xu, H., Sheng, J., et al. (2016) · Medical Science Monitor · doi:10.12659/msm.898218 · Cited by 74
“Several leukocyte subsets, such as M2 macrophages, may have an anti-inflammatory function, aid in removal of debris from damaged tissue to initiate tissue repair, and suppress fibrosis [37].”
BackgroundEichenfield, D. Z., Troutman, T. D., Link, V. M., Lam, M. T. Y., Cho, H., Gosselin, D., Spann, N. J., Lesch, H. P., Tao, J., Muto, J., et al. (2016) · eLife · doi:10.7554/elife.13024 · Cited by 75
Liu, X., Liu, Y., Zhao, L.-L., Zeng, Z., Xiao, W., & Chen, P. (2017) · Cell Biology International · doi:10.1002/cbin.10705 · Cited by 62
“Unlike M1 macrophages, M2 macrophages can attenuate the inflammatory response and promote myoblast fusion and the growth of muscle cells (Novak and Koh, 2013; Pillon et al., 2013; Tonkin et al., 2015).”
BackgroundResultThe role of immune-related myeloid cells in angiogenesis
Chambers, S. E. J., O’Neill, C. L., O’Doherty, T. M., Medina, R. J., & Stitt, A. W. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.06.010 · Cited by 73
“Recent reviews have discussed in detail the role of macrophages in tissue repair and chronic inflammation (Mantovani et al. 2013; Novak and Koh 2013); therefore, this review will focus in examining the role that myeloid cells, including macrophages, play in vascular repair and cancer (Table 1).”
BackgroundNLRP3 inflammasome activity is required for wound healing after burns
Vinaik, R., Abdullahi, A., Barayan, D., & Jeschke, M. G. (2019) · Translational research · doi:10.1016/j.trsl.2019.11.002 · Cited by 74
“Macrophage populations change from an early pro- to an anti-inflammatory phenotype as healing progresses, and impaired wound healing can be ascribed to dysregulation of macrophage polarization [11].”
BackgroundCarroll, M. J., Fogg, K. C., Patel, H. A., Krause, H. B., Mancha, A.-S., Patankar, M. S., Weisman, P. S., Barroilhet, L. M., & Kreeger, P. K. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3341 · Cited by 73
“In contrast to pro-inflammatory, classically activated macrophages (CAMs), AAMs possess a pro-tumor, anti-inflammatory phenotype and have been linked to remodeling behaviors in vivo such as wound healing and tumor progression (5,6).”
BackgroundLeung, G., Baggott, C., West, C. M., Elboim, C., Paul, S. M., Cooper, B. A., Abrams, G., Dhruva, A., Schmidt, B. L., Kober, K. M., et al. (2014) · Lymphatic Research and Biology · doi:10.1089/lrb.2013.0024 · Cited by 70
“45 One can hypothesize that dysregulation in the production of IL4 could lead to the development of soft tissue fibrosis and lymphatic dysfunction associated with LE.”
Liu, W., Zhang, F., Yan, Y., Zhang, C., Zhao, H., Heng, B. C., Huang, Y., Shen, Y., Jinxing, Z., Chen, L., et al. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202006226 · Cited by 72
Syndecan-4 enhances PDGF-BB activity in diabetic wound healing
Das, S., Majid, M., & Baker, A. B. (2016) · Acta Biomaterialia · doi:10.1016/j.actbio.2016.07.001 · Cited by 73
Soldano, S., Pizzorni, C., Paolino, S., Trombetta, A. C., Montagna, P., Brizzolara, R., Ruaro, B., Sulli, A., & Cutolo, M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166433 · Cited by 75
Laplante, P., Brillant-Marquis, F., Brissette, M.-J., Joannette-Pilon, B., Cayrol, R., Kokta, V., & Cailhier, J. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.04.030 · Cited by 68
“Macrophage plasticity is a concept widely accepted in numerous physiological states such as tissue repair, where macrophage heterogeneity, in response to specific environmental cues, orchestrates tissue healing and repair (Novak and Koh, 2013).”
BackgroundRole of wound microbiome, strategies of microbiota delivery system and clinical management
Tang, Q., Xue, N., Ding, X., Tsai, K. H. ‐., Hew, J. J., Jiang, R., Huang, R., Cheng, X., Ding, X., Cheng, Y. Y., et al. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114671 · Cited by 74
Insight into Reepithelialization: How Do Mesenchymal Stem Cells Perform?
Chen, D., Hao, H., Fu, X., & Han, W. (2015) · Stem Cells International · doi:10.1155/2016/6120173 · Cited by 71
“[47] M.”
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
“The traditional view was that less inflammation results in optimal healing with minimum scar formation, as described in mucosal or foetal wound healing,19–21 and increased inflammatory response has been linked to HS formation.(22) By contrast, Broek et al(15) found that inflammation had been suppressed in HS, compared…”
BackgroundDirect and Indirect Roles of Macrophages in Hypertrophic Scar Formation
Feng, Y., Sun, Z., Liu, S., Wu, J., Zhao, B.-H., Lv, G., Du, Y., Yu, S., Yang, M., Yuan, F., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01101 · Cited by 72
ten Brink, T., Damanik, F., Rotmans, J. I., & Moroni, L. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202301939 · Cited by 71
Human and mouse skeletal muscle stem and progenitor cells in health and disease
Mierzejewski, B., Archacka, K., Grabowska, I., Florkowska, A., Ciemerych, M. A., & Brzóska, E. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.01.004 · Cited by 70
Impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering
Isaac, A., Phillips, S. Y. R., Ruben, E., Estes, M. D., Rajavel, V., Baig, T., Paleti, C., Landsgaard, K. A., Lee, R. H., Guda, T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46327-3 · Cited by 69
“IL-6 is secreted by activated macrophages in response to injury 57,58 and plays a crucial role in osteogenic outcomes 59 .”
Xu, Y., Ying, L., Lang, J. K., Hinz, B., & Zhao, R. (2024) · Science Advances · doi:10.1126/sciadv.adj9559 · Cited by 67
Li, Y., Wu, H. C., Ji, B., Qian, W., Xia, S., Wang, L., Xu, Y., Chen, J., Yang, L. P. H., & Mao, H. Z. (2020) · ACS Applied Bio Materials · doi:10.1021/acsabm.0c00368 · Cited by 69
Macrophages in Transplantation: A Matter of Plasticity, Polarization, and Diversity
Panzer, S. E. (2021) · Transplantation · doi:10.1097/tp.0000000000003804 · Cited by 70
“Arg-1 catalyzes substrates, such as ornithine (a substrate for polyamines and collagen), to promote fibrosis and wound healing.(18) M2 macrophages produce TGFβ and platelet-derived growth factor, key mediators of fibrosis.”
BackgroundGuo, R., Merkel, A. R., Sterling, J. A. R., Davidson, J. M., & Guelcher, S. A. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.09.005 · Cited by 67
“Recent studies have reported that both M1 and M2 macrophage phenotypes are prese nt throughout the wound healing process, but the relative ratio of regenerative (M2 ) to inflammatory (M1) macrophages contributes to wound healing outcomes [20, 21].”
BackgroundMitochondria in monocytes and macrophages-implications for translational and basic research
Ravi, S., Mitchell, T., Kramer, P. A., Chacko, B. K., & Darley-Usmar, V. M. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.05.019 · Cited by 69
“M2 macrophages are antiinflammatory in nature and secrete cytokines such as IL-10, IL-4 and TGF-β to aid in wound repair and healing (Martinez et al., 2008, Novak and Koh, 2013).”
BackgroundThe Development of Macrophage-Mediated Cell Therapy to Improve Skeletal Muscle Function after Injury
Rybalko, V. Y., Hsieh, P.-L., Merscham-Banda, M., Suggs, L., & Farrar, R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0145550 · Cited by 55
“Due to incredible MP plasticity, mixed MP phenotypes are commonly identified in vivo, which makes sub-typing and classification of macrophages very complex [25, 36].”
BackgroundArchacka, K., Grabowska, I., Mierzejewski, B., Graffstein, J., Górzyńska, A., Krawczyk, M., Różycka, A. M., Kalaszczyńska, I., Muras, G., Stremińska, W., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02530-3 · Cited by 68
Udalova, I., Monaco, C., Nanchahal, J., & Feldmann, M. (2016) · Microbiology spectrum · doi:10.1128/microbiolspec.mchd-0022-2015 · Cited by 20
“In particular, M2a macrophages may not necessarily predominate in vivo during tissue repair (83).”
BackgroundBioscaffold-Induced Brain Tissue Regeneration
Modo, M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01156 · Cited by 66
“, 2017b), but this might merely be a reflection of the activating signals rather than the cells’ function (Novak and Koh, 2013).”
BackgroundChen, Y., Huang, X., Liu, A., Fan, S., Liu, S., Li, Z., Yang, X., Guo, H., Wu, M., Liu, M., et al. (2024) · Advanced Science · doi:10.1002/advs.202309725 · Cited by 65
Tailoring the immuno-responsiveness of anodized nano-engineered titanium implants
Gulati, K., Hamlet, S. M., & Ivanovski, S. (2018) · Journal of Materials Chemistry B · doi:10.1039/c8tb00450a · Cited by 63
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
Li, J., Zhang, Y., Lv, Z.-Y., Liu, K., Meng, C.-X., Zou, B., Li, K., Liu, F., & Zhang, B. (2020) · Regenerative Biomaterials · doi:10.1093/rb/rbz053 · Cited by 63
The Epidermal Keratinocyte as a Therapeutic Target for Management of Diabetic Wounds
Fang, W., & Lan, C.-C. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054290 · Cited by 70
“Actually, macrophages can coexpress both M1 and M2 markers during different stages of wound healing [27,28].”
BackgroundMoore, L. B., Sawyer, A. J., Charokopos, A., Skokos, E. A., & Kyriakides, T. R. (2014) · Acta Biomaterialia · doi:10.1016/j.actbio.2014.09.022 · Cited by 62
“that reflects spatiotemporal cues and differs between species [7].”
Wounds under diabetic milieu: The role of immune cellar components and signaling pathways
Lin, S., Wang, Q., Huang, X., Feng, J., Wang, Y., Shao, T., Deng, X., Cao, Y., Chen, X.-H., Zhou, M., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114052 · Cited by 62
Yang, Z., He, C., He, J., Chu, J., Liu, H., & Deng, X. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-0768-6 · Cited by 61
Interactions between macrophages and helminths
Coakley, G., & Harris, N. L. (2020) · Parasite Immunology · doi:10.1111/pim.12717 · Cited by 59
Kim, T. H., Jung, Y., & Kim, S. H. (2017) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0318 · Cited by 60
“53 The M2 macrophages produced by IL-4, IL-10, IL-13, or tumor necrosis factor-b are anti-inflammatory macrophage phenotype and function in wound repair through ECM deposition revascularization and wound reepithelialization.”
Malaviya, R., Sunil, V. R., Venosa, A., Verissimo, V. L., Cervelli, J. A., Vayas, K. N., Hall, L., Laskin, J. D., & Laskin, D. L. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv161 · Cited by 59
“The accumulation of each of these M1 macrophage populations in the lung was suppressed by anti-TNFa antibody, in accord with the proinflammatory M1 inducing actions of TNFa (Aggarwal et al., 2014; Novak and Koh, 2013).”
BackgroundResultWang, X., Zhao, W., Ransohoff, R. M., & Zhou, L. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.01.004 · Cited by 58
“This hypothesis was challenged by a study of traumatic muscle injury which showed that muscle macrophages upregulated both M1 and M2 genes after muscle laceration (Novak and Koh, 2013; Novak et al., 2014).”
Resolution of bleomycin-induced murine pulmonary fibrosis via a splenic lymphocyte subpopulation
Kamio, K., Azuma, A., Matsuda, K., Usuki, J., Inomata, M., Morinaga, A., Kashiwada, T., Nishijima, N., Itakura, S., Kokuho, N., et al. (2018) · Respiratory Research · doi:10.1186/s12931-018-0783-2 · Cited by 58
“Furthermore, we assayed macrophage subpopulations because diverse activation states of macrophages can result in phenotypic polarization and the formation of pro-inflammatory M1 and pro-healing M2 type macrophages [20].”
MethodPlatelet-rich plasma promotes recruitment of macrophages in the process of tendon healing
Nishio, H., Saita, Y., Kobayashi, Y., Takaku, T., Fukusato, S., Uchino, S., Wakayama, T., Ikeda, H., & Kaneko, K. (2020) · Regenerative Therapy · doi:10.1016/j.reth.2020.03.009 · Cited by 58
Mukhtar, M., Ali, H., Ahmed, N., Munir, R., Talib, S., Khan, A. S., & Ambrus, R. (2020) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2020.1783237 · Cited by 54
Monocyte/Macrophage Heterogeneity during Skin Wound Healing in Mice
Pang, J., Maienschein‐Cline, M., & Koh, T. J. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2200365 · Cited by 53
Self-citationM1 Macrophages Activate Notch Signalling in Epithelial Cells: Relevance in Crohn’s Disease
Ortiz‐Masiá, D., Cosín‐Roger, J., Calatayud, S., et al. (2016) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjw009 · Cited by 55
Biomedical Implant Capsule Formation
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“As discussed previously, macrophages can have diverse roles in wound healing processes.(134)”
BackgroundTLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair
Natarajan, C., Yao, S., & Sriram, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152163 · Cited by 55
“Macrophages adopt two broadly exclusive phenotypes, depending upon the stimuli they receive [14, 29, 30].”
BackgroundThe acute inflammatory response of teleost fish
Soliman, A. M., & Barreda, D. R. (2023) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2023.104731 · Cited by 56
Torres, M. M., Wang, J., Yannie, P. J., Ghosh, S., Segal, R. A., & Reynolds, A. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007172 · Cited by 55
“M1s are assumed to be able to switch to M2s at rate km1m2, and this switch is assumed to be promoted by the phagocytosis of apoptotic cells [1, 3, 42, 46].”
BackgroundEnhanced Biological Activity of a Novel Preparation of Lavandula angustifolia Essential Oil
Miastkowska, M. A., Kantyka, T., Bielecka, E., Kałucka, U., Kamińska, M., Kucharska, M., Kilanowicz, A., Cudzik, D., & Cudzik, K. (2021) · Molecules · doi:10.3390/molecules26092458 · Cited by 52
“At the same time, VEGF promotes macrophage polarization and the proregenerative phenotype of M2 [47], while the reduced levels of VEGF correlate with the predominance of the proinflammatory phenotype of M1 and reduced phagocytosis of apoptotic neutrophils in diabetic wounds [48,49].”
BackgroundMoore, J. K., MacKinnon, A. C., Wojtacha, D., Pope, C., Fraser, A. R., Burgoyne, P., Bailey, L., Pass, C., Atkinson, A. P. M., McGowan, N. W. A., et al. (2015) · Cytotherapy · doi:10.1016/j.jcyt.2015.07.016 · Cited by 52
“This phenotypic profile is indicative of disease resolution macrophages identified in the previous models of liver disease and in other pathologies [43,44].”
The Effects of M1 and M2 Macrophages on Odontogenic Differentiation of Human Dental Pulp Cells
Park, H. C., Quan, H., Zhu, T., Kim, Y., Kim, B., & Yang, H. (2017) · Journal of Endodontics · doi:10.1016/j.joen.2016.11.003 · Cited by 51
“The precise effect of M2 macrophages on pulp cells has yet to be revealed despite the considerable amount of evidence of their critical role in the general wound healing process (15, 16).”
BackgroundBiomaterials‐Based Technologies in Skeletal Muscle Tissue Engineering
Luo, W., Zhang, H., Wan, R., Cai, Y., Liu, Y., Wu, Y., Yang, Y., Chen, J., Zhang, D., Luo, Z., et al. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202304196 · Cited by 53
Cellular crosstalk in fibrosis: Insights into macrophage and fibroblast dynamics
Froom, Z. S. C. S., Callaghan, N. I., & Huyer, L. D. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110203 · Cited by 64
“The complexity of the fi brotic microenvironment can be attributed to a high degree of overlap within these pathways that is exacerbated by chronic activation, which may modulate the intended functional changes into a pathological outcome (39, 94).”
Macrophage polarization in kidney diseases
Tian, S., & Chen, S. (2015) · Macrophage · doi:10.14800/macrophage.679 · Cited by 51
“M1 or M2-associated markers may also be expressed simultaneously by the tissue macrophages ([61]).”
BackgroundSousa, K. D. B., Rodrigues, M. F. S. D., Santos, D. D. S., Mesquita‐Ferrari, R. A., Nunes, F. D., da Silva, D. D. F. T., Bussadori, S. K., & Fernandes, K. P. S. (2019) · Lasers in Medical Science · doi:10.1007/s10103-019-02817-1 · Cited by 56
Alginate-based biomaterial-mediated regulation of macrophages in bone tissue engineering
Li, Y., Xu, Z., Wang, J., Pei, X., Chen, J., & Wan, Q. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.123246 · Cited by 52
Metadata
- Authors
- Novak, M. L., & Koh, T. J.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Koh, Timothy J
- ORCID
- Koh, Timothy J
- Venue
- Journal of Leukocyte Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-03-15
- Volume
- 93
- Issue
- 6
- Pages
- 875-881
- ISSN
- 0741-5400 (ISSN-L)
- 1938-3673
- PMC
- PMC3656331
- OpenAlex
- W2159442019
- Semantic Scholar
- 32d24c1f92ce6e25fe1a62057f0c92ea3227742b
- Cited by
- 658
- References
- 85
- Citations by year
- 2026: 29 · 2025: 52 · 2024: 61 · 2023: 47 · 2022: 59 · 2021: 75 · 2020: 50 · 2019: 46 · 2018: 45 · 2017: 47 · 2016: 54 · 2015: 52 · 2014: 29 · 2013: 10
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Leukocyte Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Defense (#W81XWH-05-1-0159)
- U.S. National Institutes of Health (#R01GM092850)
- American College of Sports Medicine Doctoral Student Research (#2011-03604-00-00)
- University of Illinois at Chicago Graduate College Dean’s Scholar Award
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- macrophage phenotype, tissue repair, M1 macrophages, M2 macrophages, wound healing, macrophage heterogeneity, macrophage polarization, inflammatory macrophages, anti-inflammatory macrophages, fibrosis, macrophage markers
- MeSH terms
- Animals, Humans, Macrophages, Phenotype, Regeneration, Wound Healing
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