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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
36 Own interpretation · 33 Not checked yet · 11 No basis given · 1 Own result
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
plaindirect- Asserted: passes — The authors put it forward as true.
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In 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]
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In 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
hedged- 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
“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
plain- Asserted: passes — The authors put it forward as true.
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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
plain- 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
“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
plain- 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
“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
hedged- 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
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- 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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably 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
plain- Asserted: passes — The authors put it forward as true.
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It 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
plain- Asserted: passes — The authors put it forward as true.
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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
“two of the best-characterized in vitro phenotypes are a proinflammatory”
§ Macrophage phenotypes during tissue repair > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably 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]
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
“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
plain- Asserted: passes — The authors put it forward as true.
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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
“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
hedgedconditional- 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
“In numerous physiological and pathological states, Mp exhibit extensive heterogeneity and plasticity, and tissue repair is no exception.”
§ Macrophage phenotypes during tissue repair > Introduction
plain- 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
“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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
hedged- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plain- 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
“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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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- 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
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
“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
plain- Asserted: passes — The authors put it forward as true.
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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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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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
plaincorrelational- 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 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably 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
hedgedconditional- 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.
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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
“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
hedged- 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.
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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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
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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.
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In the paper
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
“TGF- increases with time (skin); IL-10 time course not known.”
§ Macrophage phenotypes during tissue repair > Mp PHENOTYPES DURING TISSUE REPAIR AND FIBROSIS
“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].”
Citations
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Items 301–400 of 654
Saito, T., Hasegawa‐Moriyama, M., Kurimoto, T., Yamada, T., Inada, E., & Kanmura, Y. (2015) · Anesthesiology · doi:10.1097/aln.0000000000000892 · Cited by 26
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“M1 macrophages are characterized by their expression of high levels of proinflammatory cytokines, which exacerbate tissue injury,(23) whereas M2 macrophages are responsible for inflammation resolution and wound repair.(24) That macrophage polarization can be affected by the depletion of neutrophils(25) suggests an int…”
BackgroundNLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice
Zhao, J., Zhang, S., Gong, Z., Mao, W., Bao, W., Li, Q., Bai, Y., Gao, F., & Feng, S. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02063-9 · Cited by 32
Chen, L., Zhang, Q., Chen, Q., Ran, F.-Y., Yu, L., Liu, X., Fu, Q., Song, G., Tang, J., & Zhang, T. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00579 · Cited by 26
“Macrophage activation and phenotypic switch from macrophages (M0) to a pro-inflammatory phenotype (M1) and anti-inflammatory phenotype (M2) are involved in the inflammatory response and development of various human diseases, such as heart disease, diabetes mellitus, and Alzheimer’s disease (Novak and Koh, 2013).”
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Amphiphilic galactomannan nanoparticles trigger the alternative activation of murine macrophages
Peled, E., & Sosnik, A. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.10.017 · Cited by 24
Martin, K. S., Virgilio, K. M., Peirce, S., & Blemker, S. (2016) · Cells Tissues Organs · doi:10.1159/000443635 · Cited by 18
Du, S., Zhou, Y., Hu, H., Li, L., & Zhang, Z. (2024) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2024.2400323 · Cited by 25
“They can promote collagen synthesis and deposition (Novak and Koh 2013; Lodyga et al. 2019).”
Chen, M., Qiao, Y., Yu, L., Wang, W., Wang, W., Sun, H., Xu, Y., Bai, J., Zhou, J., & Geng, D. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.09.017 · Cited by 26
“Specifically, M1 macrophages release proinflammatory mediators including interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α ) to induce inflammation [60].”
BackgroundLiao, Y., Ivanova, L. B., Zhu, H., Yahr, A., Ayello, J. S., van de Ven, C., Rashad, A., Uitto, J., Christiano, A. M., & Cairo, M. S. (2015) · Stem Cells · doi:10.1002/stem.1966 · Cited by 27
High-Performance Acellular Tissue Scaffold Combined with Hydrogel Polymers for Regenerative Medicine
Lee, E., Kim, H. J., Shaker, M. R., Ryu, J. R., Ham, M. S., Seo, S. H., Kim, D. H., Lee, K., Jung, N., Choe, Y., et al. (2019) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.9b00219 · Cited by 24
Naoxintong accelerates diabetic wound healing by attenuating inflammatory response
Fang, L., Chen, L., Song, M., He, J., Zhang, L.-S., Li, C.-X., Wang, Q., Yang, W., Sun, W., Leng, Y., et al. (2021) · Pharmaceutical Biology · doi:10.1080/13880209.2021.1877735 · Cited by 25
Biomaterial Strategies to Bolster Neural Stem Cell-Mediated Repair of the Central Nervous System
Tejeda, G., Ciciriello, A. J., & Dumont, C. M. (2021) · Cells Tissues Organs · doi:10.1159/000515351 · Cited by 28
“Macrophages and microglia, the resident CNS macrophage, exist on a nuanced spectrum of phenotypes that are often simplified to being pro-inflammatory (M1) or pro-regenerative (M2) [Mosser and Edwards, 2008; Novak and Koh, 2013].”
BackgroundInnate immunity and immunotherapy for hemorrhagic shock
Huang, Q., Gao, S., Yao, Y., Wang, Y., Li, J., Chen, J., Chen, G., Zhao, D., & Li, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.918380 · Cited by 26
“CSF, TNF-a, and interferon-g), to M2-type macrophages, polarized by Th2 cytokines (IL-4 and IL-13) to deal with tissue repair (24, 25).”
BackgroundKeeler, G. D., Durdik, J. M., & Stenken, J. A. (2014) · Acta Biomaterialia · doi:10.1016/j.actbio.2014.10.022 · Cited by 25
“M2a macrophages are characterized as producing collagen type VI, fibronectin, transforming growth factor beta (TGF-b) and transforming growth factor beta induced (TGFbI) [8].”
BackgroundHematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages
Batugedara, H., Li, J., Chen, G., Lu, D., Patel, J. J., Jang, J. C., Radecki, K. C., Burr, A. C., Lo, D. D., Dillman, A. R., et al. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.4a0917-369rr · Cited by 25
Mahmoudi, N., Mohamed, E., Dehnavi, S. S., Aguilar, L. M. C., Harvey, A. R., Parish, C. L., Williams, R. J., & Nisbet, D. R. (2023) · Advanced Science · doi:10.1002/advs.202303707 · Cited by 23
Macrophage autophagy protects mice from cerium oxide nanoparticle-induced lung fibrosis
Annangi, B., Lu, Z., Bruniaux, J., Ridoux, A., da Silva, V. M., Vantelon, D., Boczkowski, J., & Lanone, S. (2021) · Particle and Fibre Toxicology · doi:10.1186/s12989-021-00398-y · Cited by 24
Aokage, T., Seya, M., Hirayama, T., Nojima, T., Iketani, M., Aoyama-Ishikawa, M., Terasaki, Y., Taniguchi, A., Miyahara, N., Nakao, A., et al. (2021) · BMC Pulmonary Medicine · doi:10.1186/s12890-021-01712-2 · Cited by 25
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“In early studies, cell behaviors such as migration and differentiation were simulated using continuum models (Bailón‐Plaza & Van Der Meulen, 2001, 2003) and lattice‐ based models (Checa & Prendergast, 2009; Pérez & Prendergast, 2007; Sandino et al., 2010).”
MethodWu, W., Zhang, G., Qiu, L., Liu, X., Zhou, S. F., & Wu, J. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/5265616 · Cited by 24
“Macrophages can be di ff erentiated into two distinct subpopulations, namely, as classically activated proin-fl ammatory M1 phenotype and alternatively activated (M2) phenotype accounting for anti-in fl ammation and tissue repair [14].”
Dai, X., Xu, Q., Li, Y., Yang, L., Zhang, Y. J., Liu, X., & Gao, F. (2023) · Chemical Engineering Journal · doi:10.1016/j.cej.2023.144694 · Cited by 22
Mohrman, A. E., Farrag, M., Huang, H., et al. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4341 · Cited by 23
“Important cellular markers of each M1, M2a, M2b, and M2c polarization phase were selected based on commonality in the literature and detection in our dataset (macrophage polarization is reviewed in 29–31 ).”
Liao, C.-F., Chen, C.-C., Lu, Y.-W., Yao, C., Lin, J., Way, T., Yang, T.-Y., & Chen, Y.-S. (2019) · Journal of Biological Engineering · doi:10.1186/s13036-019-0216-x · Cited by 24
Response of macrophages in rat skeletal muscle after eccentric exercise
Zuo, Q., Wang, S., Yu, X., & Chao, W. (2018) · Chinese journal of traumatology = Zhonghua chuang shang za zhi · doi:10.1016/j.cjtee.2017.12.001 · Cited by 19
Hematopoietic Stem Cells in Wound Healing Response
Urao, N., Liu, J., Takahashi, K., & Ganesh, G. (2021) · Advances in Wound Care · doi:10.1089/wound.2021.0065 · Cited by 23
“Timely phase transition from the inflammatory phase involves phenotypic switch of myeloid cells, which have often been described in the overly simplified M1 versus M2 polarization of macrophages.(15) Similar proinflammatory versus anti-inflammatory polarization has been proposed in neutrophils (N1 vs.”
BackgroundLiu, J., Li, F., Ouyang, Y., Su, Z., Chen, D., Liang, Z., Zhang, Z., Lin, R., Luo, T., & Guo, L. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.109890 · Cited by 25
Myricetin alleviates DNCB-induced atopic dermatitis by modulating macrophage M1/M2 polarization
Zhang, X., Li, J., Liu, Y., Ma, R., Li, C., Xu, Z., Wang, R., Zhang, L., & Zhang, Y. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115212 · Cited by 22
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“M2 macrophages are generally involved in tissue healing, regeneration, and remodeling, mediated through the expression of anti-inflammatory molecules [7].”
BackgroundGalvão-Lima, L. J., Espíndola, M. S., Soares, L. S., Zambuzi, F. A., Cacemiro, M. D. C., Fontanari, C., Bóllela, V. R., & Frantz, F. G. (2016) · The Brazilian Journal of Infectious Diseases · doi:10.1016/j.bjid.2016.10.004 · Cited by 21
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Liu, X., Zeng, Z., Zhao, L., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00601 · Cited by 20
“These M1 macrophages infiltrate injury sites following muscle damage and are involved in the phagocytosis of muscle debris (Novak and Koh, 2013).”
BackgroundWei, Y., Yun, X., Guan, Y., Cao, S., Li, X., Wang, Y., Meng, H., Liu, Y.-J., Quan, Q., & Wei, M. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.2c20386 · Cited by 24
ECM-inspired calcium/zinc laden cellulose scaffold for enhanced bone regeneration
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Regulatory T cells and macrophages in atherosclerosis: from mechanisms to clinical significance
Ouyang, X., & Liu, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1435021 · Cited by 20
“M2a macrophages have been described as “ wound-healing ” or “ tissue-repairing ” macrophages, which promote the deposition of extracellular matrix by the release of TGF-b (32, 35).”
Pro-healing impact of liraglutide on skin wounds in normoglycemic mice
Han, Y., Zhang, X., Zhao, Z., Gong, S., & Shao, S. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114050 · Cited by 19
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The Role of CD28 and CD8+ T Cells in Keloid Development
Shan, M., Liu, H., Hao, Y., Song, K., Feng, C., & Wang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168862 · Cited by 21
“M2 macrophages are the main macrophage population in the advanced hyperplasia and remodeling stage of keloids [49].”
BackgroundTumor‐associated macrophages‐educated reparative macrophages promote diabetic wound healing
Mu, R., Zhang, Z., Han, C., Niu, Y., Xing, Z., Liao, Z., Xu, J., Shao, N., Chen, G., Zhang, J., et al. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202216671 · Cited by 19
“…skin repair, macrophages change their phenotypes at the right timing to exert sequential activities, exhibiting a delicate balance of pro- and anti-inflammatory characteristics to drive angiogenesis (Eming et al, 2014), promote cell proliferation, and modulate inflammation (Novak & Koh, 2013).”
BackgroundSavić, R., Yang, J., Koplev, S., An, M. C., Patel, P. L., O’Brien, R., Dubose, B. N., Dodatko, T., Rogatsky, E., Sukhavasi, K., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113371 · Cited by 21
“45 Together our data suggest that in the context of senescence, reduced COL6A3 signals from the liver may differentially influence immune cell phenotypes of the adipose and blood depots, which in turn could impact homeostatic functions in those target tissues.”
BackgroundZheng, X., Qiu, J., Ye, J., Gong, Y., Jiang, T., Gao, N., Jiang, C., Chu, B., Zhang, W., Li, Z., et al. (2024) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2024.05.001 · Cited by 20
He, Y., Tang, Y., Zeng, B., Chen, X., Yuan, L., Lu, Y., Du, W., Li, R., Han, Y., Deng, F., et al. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101122 · Cited by 20
“Macrophages tend to polarize towards the M1 phenotype in the in fl ammation phase, and increase the secretion of pro-in fl ammatory cytokines such as TNF α , IL1 β , and iNOS, which can exacerbate harmful inflammatory responses [51,60].”
BackgroundPalatogenesis and cutaneous repair: A two‐headed coin
Biggs, L. C., Goudy, S. L., & Dunnwald, M. (2014) · Developmental Dynamics · doi:10.1002/dvdy.24224 · Cited by 19
“Monocytes appear in two waves: the first one is immediate, resulting from “inflammatory monocytes” while the second consists of tissue resident-derived monocytes that arrive after homing to inflammation (Novak and Koh, 2013).”
BackgroundModeling osteoinduction in titanium bone scaffold with a representative channel structure
He, S., Zhang, Y., Zhou, Y., Bao, N., Cai, Y., Zhou, P., Wang, P., Li, L., & Jiang, Q. Y. (2020) · Materials Science and Engineering C · doi:10.1016/j.msec.2020.111347 · Cited by 19
Nikovics, K., Morin, H., Riccobono, D., Bendahmane, A., & Favier, A. (2020) · The FASEB Journal · doi:10.1096/fj.202001496r · Cited by 20
Stem Cell Secretome for Spinal Cord Repair: Is It More than Just a Random Baseline Set of Factors?
Pajer, K., Bellák, T., & Nógrádi, A. (2021) · Cells · doi:10.3390/cells10113214 · Cited by 21
Xie, X., Xu, J., Ding, D., et al. (2024) · Nano Letters · doi:10.1021/acs.nanolett.4c00818 · Cited by 18
Tumor-associated macrophages affect the treatment of lung cancer
Yu, Z., Zou, J., & Xu, F. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29332 · Cited by 22
Mendoza‐Novelo, B., Castellano, L. E., Padilla‐Miranda, R. G., Lona‐Ramos, M. C., Cuéllar‐Mata, P., Vega‐González, A., Murguía‐Pérez, M., Mata‐Mata, J. L., & Ávila, E. E. (2016) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.35825 · Cited by 18
Nakayama, M., Zhu, W.-J., Watanabe, K., et al. (2017) · BMC Nephrology · doi:10.1186/s12882-017-0741-0 · Cited by 18
“, M1 macrophages have inflammatory actions, and M2 have remodeling/healing actions in damaged tissues [24].”
BackgroundWound Healing in the Oral Mucosa
Smith, P. C., & Martínez, C. (2018) · Springer eBooks · doi:10.1007/978-3-319-56065-6_6 · Cited by 19
Fang, M. M., Barman, P. K., Thiruppathi, M., Mirza, R. E., McKinney, R. D., Deng, J., Christman, J. W., Du, X., Fukai, T., Ennis, W. J., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800252 · Cited by 18
“This acute inflammatory myeloid response is followed by its resolution during normal wound healing (41).”
BackgroundSelf-citationResponse of Human Macrophages to Clinically Applied Wound Dressings Loaded With Silver
Varela, P., Marlinghaus, L., Sartori, S., Viebahn, R., Salber, J., & Ciardelli, G. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00124 · Cited by 19
“The following antibodies were added to cells suspended in 1.5% paraformaldehyde (PFA): FITClabeled mouse anti-human CD197 (clone G043H7), PE-labeled mouse anti-human HLA-DR (clone L243), PE-labeled mouse anti-human CD163 (clone GHI/61) and FITC-labeled mouse anti-human CD206 (clone 15-2).”
BackgroundInfluentialMuscle Tissue Damage and Recovery After EV71 Infection Correspond to Dynamic Macrophage Phenotypes
Lu, M.-Y., Lin, Y.-L., Kuo, Y., Chuang, C.-F., Wang, J., & Liao, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.648184 · Cited by 16
“CD206, the mannose receptor, is a marker for tissue-resident and anti-inflammatory macrophages (20), and it is widely used to identify macrophage subsets that exhibit anti-inflammatory functions (21).”
BackgroundWang, H., Jiang, H., & Cheng, X. W. (2022) · PeerJ · doi:10.7717/peerj.12846 · Cited by 17
“According to a description from Novak & Koh (2013) , M1 macrophages are classically activated macrophages, also known as “ killer ” macrophages, and M2 macrophages are alternately activated macrophages, also known as “ therapeutic ” macrophages.”
Zhang, Y., Du, Z., Li, D., Wan, Z., Zheng, T., Zhang, X., Yu, Y., Yang, X., & Cai, Q. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2022.113269 · Cited by 18
Yamaguchi, M., Takagi, K., Miki, Y., Sato, A., Iwabuchi, E., Miyashita, M., & Suzuki, T. (2023) · Cancers · doi:10.3390/cancers15061903 · Cited by 17
“M2 macrophages are further subdivided into the M2a, M2b, and M2c phenotypes [64] and, while Komarova et al.”
BackgroundJiao, B., Zhang, Q., Jin, C., Yu, H., & Wu, Q. (2023) · Inflammation · doi:10.1007/s10753-023-01890-7 · Cited by 18
“Macrophage polarization related to immune response is an important mechanism of pulmonary fibrosis [33].”
Huang, C., Wang, L., Lue, J., Chen, S., & Tsai, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116769 · Cited by 19
Son, M., Kang, W. C., Oh, S., Bayarsaikhan, D., Ahn, H., Lee, J., Park, H., Lee, S., Choi, J., Lee, H. S., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-11773-1 · Cited by 17
Cheng, Y., Luo, D., Zhao, Y., & Rong, J. (2020) · Aging · doi:10.18632/aging.102959 · Cited by 18
“The overactivation of M1 macrophage polarization causes tissue damages whereas the delay of macrophage polarization towards a pro-resolving macrophage phenotype may impair tissue repair [35].”
BackgroundMonocyte M1 / M2 profile is altered in paediatric burn patients with hypertrophic scarring
Williams, H., Suda, S., Dervish, S., Yap, Y. T., Holland, A. J. A., & Medbury, H. J. (2021) · Wound Repair and Regeneration · doi:10.1111/wrr.12960 · Cited by 16
The Evolving Function of Vasculature and Pro-angiogenic Therapy in Fat Grafting
Xining, Z., & Luo, S. (2024) · Cell Transplantation · doi:10.1177/09636897241264976 · Cited by 18
“Numerous factors in fat grafting contribute to the enhancement of M2 macrophage polarization (as depicted in the figure), indirectly fostering angiogenesis and shifting the pro-inflammatory microenvironment toward an anti-inflammatory state post-fat grafting 65–67 .”
BackgroundPericytes in Cutaneous Wound Healing
Morikawa, S., Iribar, H., Gutiérrez‐Rivera, A., Ezaki, T., & Izeta, A. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-16908-4_1 · Cited by 17
Role of bone marrow-derived macrophages (BMDMs) in neurovascular interactions during stroke
Srivastava, A., Srivastava, P., & Verma, R. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104480 · Cited by 16
Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo
Markov, A. V., Васильевна, С. А., Babich, V. O., Odarenko, K. V., Talyshev, V. A., Salomatina, O. V., Salakhutdinov, N. F., Аркадьевна, З. М., & Logashenko, E. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217876 · Cited by 16
“In response to these stimuli, macrophages are activated, which allows them to combat pathogens, exert an immunomodulatory role, and maintain tissue integrity [2,6,7].”
BackgroundAli, H., Caballero, R. E., Dong, S. X. M., Gajnayaka, N., Vranjkovic, A., Ahmed, D., Iqbal, S., Crawley, A. M., Angel, J. B., Cassol, E., et al. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.4a0220-114rr · Cited by 16
Cakmak, B., Saglam‐Metiner, P., Beceren, G., Zhang, Y. S., & Yeşil-Çeliktaş, Ö. (2022) · Bio-Design and Manufacturing · doi:10.1007/s42242-022-00198-z · Cited by 15
“In addition,M2b is induced by LPS, unlike the M2a and M2c subtypes of M2 macrophages [76].”
BackgroundHe, M., Yang, B., Huo, F., Xie, L., Yang, M., & Tian, W. (2021) · Journal of Materials Chemistry B · doi:10.1039/d1tb00953b · Cited by 16
The microenvironment of secondary lymphedema. The key to finding effective treatments?
Hossain, L., Gomes, K. P., Safarpour, S., & Gibson, S. B. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167677 · Cited by 17
Insights Into Macrophage Polarization and M1 / M2 Balance in Diabetic Foot Ulcers
Zhang, J., Li, H., Dong, Y., Zhou, Z., Wang, Y., Chen, X., & Cai, Y. (2026) · Journal of Diabetes · doi:10.1111/1753-0407.70205 · Cited by 18
Parsi, S., Zhu, C., Motlagh, N. J., Kim, D., Kuellenberg, E. G., Kim, H.-H., Gillani, R. L., & Chen, J. W. (2024) · Magnetic Resonance Imaging Clinics of North America · doi:10.1016/j.mric.2024.01.003 · Cited by 15
Biology of Renal Recovery: Molecules, Mechanisms, and Pathways
Vincent, I., & Okusa, M. D. (2014) · Nephron Clinical Practice · doi:10.1159/000363714 · Cited by 15
Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung
Zhong, Q., Jenkins, J., Moldobaeva, A., D’Alessio, F. R., & Wagner, E. M. (2015) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2015-0087oc · Cited by 15
Metabolic regulation of innate immune cell phenotypes during wound repair and regeneration
Aloysius, A., Saxena, S., & Seifert, A. W. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.10.012 · Cited by 16
Wu, C., Tsai, H., Su, Y., Tsai, C.-Y., Lu, Y., & Lin, C. (2022) · Cells · doi:10.3390/cells11020242 · Cited by 16
Cantaruti, T., Costa, R. A., Souza, K. S., Vaz, N. M., & Carvalho, C. R. (2017) · Immunology · doi:10.1111/imm.12732 · Cited by 14
“IL-4 strongly activates type-2 macrophages that produce antiinflammatory cytokines such as IL-10 and TGF-1 (35, 36).”
BackgroundWang, Y., Feng, Y., Yan, J., Han, X., Song, P., Wu, Y., Wang, X., Mu, Z., Li, X., & Zhang, H. (2023) · Materials Today Nano · doi:10.1016/j.mtnano.2023.100351 · Cited by 14
Sepsis-Associated Acute Kidney Injury
Wang, D., Sun, T., & Liu, Z. (2023) · Intensive Care Research · doi:10.1007/s44231-023-00049-0 · Cited by 17
“Thus, once PAMPs or DAMPs are filtered through the glomerulus, similar pathways are activated, leading to increased oxidative stress, production of reactive oxygen species, and mitochondrial damage [27, 32–35].”
BackgroundSun, M., Zeng, Z., Xu, G., An, S. L., Deng, Z., Cheng, R., Yao, Y., Wu, J., Hu, H., Huang, Q., et al. (2023) · Shock · doi:10.1097/shk.0000000000002206 · Cited by 14
“Excessive activation of proinflammatory M1 macrophage polarization causes tissue damage, whereas delayed polarization of antiinflammatory M2 macrophages impairs tissue repair (31).”
BackgroundM2a macrophages facilitate resolution of chemically-induced colitis in TLR4-SNP mice
Vlk, A., Prantner, D., Shirey, K. A., Perkins, D. J., Buzza, M. S., Thumbigere‐Math, V., Keegan, A. D., & Vogel, S. N. (2023) · mBio · doi:10.1128/mbio.01208-23 · Cited by 17
“Mφ mediate innate immune responses to PAMPs and DAMPs and play a key role in tissue repair and regeneration (163–165).”
BackgroundShou, J., Shi, X., Liu, X., Chen, Y., Chen, P., & Xiao, W. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00542-4 · Cited by 14
“There are two basic types of macrophages, pro-inflammatory and anti-inflammatory macrophages [6, 7].”
BackgroundInteraction Between Intrinsic Renal Cells and Immune Cells in the Progression of Acute Kidney Injury
Deng, J., Wu, Z., He, Y., Lin, L., Tan, W., & Yang, J. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.954574 · Cited by 16
“Upon sensing local tissue injury, resident and infiltrating inflammatory cells in the kidney promote TEC PCD by producing and releasing large amounts of inflammatory cytokines and activating various pathway proteins, leading to TEC detachment, tubular occlusion, and tubular inactivation.”
BackgroundInfluentialSoluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages
Royzman, D., Peckert-Maier, K., Stich, L., Koenig, C., Wild, A. B., Tauchi, M., Ostalecki, C., Kiesewetter, F., Seyferth, S., Lee, G., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1012647 · Cited by 13
“This multifactorial modulation by sCD83 is further supported by the stabilized expression of YM-1, a key marker for tissue repair macrophages, which is vital for the subsequent transition towards proliferation and reepithelization (77).”
BackgroundBjurling, J., Chavkin, N. W., Halvardson, J., Thel, M. C., Mattisson, J., Kim, J. S., Zaghlool, A., Ma, S., Martínez, F. J., Anstrom, K. J., et al. (2025) · Communications Medicine · doi:10.1038/s43856-025-00966-9 · Cited by 13
The role of macrophages in renal fibrosis and therapeutic prospects
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“Their biological functions, ranging from promoting renal tissue damage to facilitating repair or driving fibrosis, are critically determined by their phenotypic polarization states and surrounding microenvironment ( Yonemoto et al., 2006 ; Calle & Hotter, 2020 ; Novak & Koh, 2013 ).”
Th1–Th2 and M1-M2 interplay sculpt Aeromonas hydrophila pathogenesis in zebrafish (Danio rerio)
Kumar, J., Kumar, M., Sharma, S., et al. (2022) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2022.06.052 · Cited by 13
Wilmes, V., Kur, I.-M., Weigert, A., Verhoff, M. A., Gradhand, E., & Kauferstein, S. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1104019 · Cited by 13
“Even though iNOS is classically viewed as a marker of infiltrating macrophages (20, 21, 25), the limitations of this nomenclature are described (21, 26, 27).”
BackgroundRhim, W.-K., Woo, J., Kim, J. Y., Lee, E. H., Cha, S.-G., Kim, D., Baek, S., Park, C. G., Kim, B. S., Kwon, T. G., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.03.018 · Cited by 15
“The macrophages have emerged as a therapeutic target for tissue regeneration due to their critical role in regulating multiple stages of tissue repair by fine-tuning the phenotypic shifts [70].”
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“M1 macrophages produce large amount of inflammatory cytokines leading to tissue damage, while M2 secrete antiinflammatory cytokines contributing tissue repair [33].”
BackgroundWessely‐Szponder, J., Szponder, T., & BOBOWIEC, R. (2017) · Research in Veterinary Science · doi:10.1016/j.rvsc.2017.05.003 · Cited by 14
The mutual regulation between γδ T cells and macrophages during wound healing
Hu, W., Zhang, X., Sheng, H., Liu, Z., Chen, Y., Huang, Y., He, W., & Luo, G. (2023) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiad087 · Cited by 13
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Adipose tissue metabolism and inflammation in obesity
van Meijel, R. L. J., Blaak, E. E., & Goossens, G. H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813553-2.00001-4 · Cited by 13
Stem cells in skeletal muscle growth and regeneration in amniotes and teleosts: Emerging themes
Ruparelia, A. A., Ratnayake, D., & Currie, P. D. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.365 · Cited by 15
“This simple duality is not an accurate representation of the true in vivo situation, where this plasticity manifests as a continuance of multiple phenotypes (Novak & Koh, 2013).”
BackgroundPhagocytosis of apoptotic endothelial cells reprograms macrophages in skin wounds
Xu, M., Chen, Z., Chen, K., Ma, D., Chen, L., & DiPietro, L. (2021) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2021.100038 · Cited by 14
Girgis, B., Carvalho, D. M., & Duarte, J. A. (2022) · Wound Repair and Regeneration · doi:10.1111/wrr.13063 · Cited by 12
1,25(OH)2D3 improves diabetic wound healing by modulating inflammation and promoting angiogenesis
Ma, Y., Gong, Y., Wu, Y. C., Zhao, Q., Fu, R., Zhang, X., Li, Y., & Zhi, X. (2024) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2024.106477 · Cited by 12
Malavazzi, T. C. D. S., Andreo, L., Martinelli, A., Rodrigues, M. F. S. D., Horliana, A. C. R. T., Bussadori, S. K., Fernandes, K. P. S., Nunes, F. D., & Mesquita‐Ferrari, R. A. (2024) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2024.112921 · Cited by 13
Transcription Factor Activity Regulating Macrophage Heterogeneity during Skin Wound Healing
Zandigohar, M., Pang, J., Rodrigues, A., Roberts, R. E., Dai, Y. D., & Koh, T. J. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2400172 · Cited by 11
Self-citation
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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