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.
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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."
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 60 cited sources checked · 0 supported · 0 flagged
- Premisenone given
Mp can adopt a variety of functional phenotypes in response to different stimuli.
“Mp can adopt a variety of functional phenotypes in response to different stimuli; two of the best-characterized in vitro phenotypes are a proinflammatory”
Quote in the paperSubstantial claim - Premisecitation
Mp are essential to regeneration, repair, and remodeling in numerous tissues.
“Mp, in particular, are known to be essential to regeneration, repair, and remodeling in numerous tissues [1][2][3][4][5].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1][2][3][4][5]
Not checked in the free run.
- Premisecitation
Chronic inflammation and persistent Mp accumulation are often associated with tissue destruction and fibrosis.
“However, chronic inflammation and persistent Mp accumulation are often associated with tissue destruction and fibrosis [6 -8].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [7] Moyer, 2011, Regeneration versus fibrosis in skeletal muscle, Curr. Opin. Rheumatol. source
Not checked in the free run.
- cites [8] Murray, 2011, Protective and pathogenic functions of macrophage subsets, Nat. Rev. Immunol. source
Not checked in the free run.
- Premisecitation
The M1-associated cytokines IL-1β, TNF-α, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin, liver, kidney, and skeletal muscle.
“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].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- cites [60] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine source
Not checked in the free run.
- cites [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 in the free run.
- cites [62] Karlmark, 2010, The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes, Hepatology source
Not checked in the free run.
- cites [63] Lee, 2011, Distinct macrophage phenotypes contribute to kidney injury and repair, J. Am. Soc. Nephrol. source
Not checked in the free run.
- Interpretationcitation
M1 and M2a/b/c are not discrete Mp differentiation states but represent convenient but limited and arbitrary in vitro-defined reference points on a time-dependent and multidimensional continuum of possible Mp phenotypes and functions.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat. Rev. Immunol. source
Not checked in the free run.
- Interpretationreasoning
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.
“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.”
Quote in the paperSubstantial claim - Premisecitation
Human M2a Mp or monocytes do not express arginase.
“Importantly, in contrast to rodent Mp, human M2a Mp or monocytes do not express arginase [36,37].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [36] Munder, 2005, Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity, Blood source
Not checked in the free run.
- cites [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
Not checked in the free run.
- Interpretationnone given
The Mp populations that participate in tissue repair are not analogous to in vitro M2a Mp.
“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.”
Quote in the paperNot a substantial claim - Interpretationnone given
Phenotypic markers that appear to be coregulated in cultured Mp can be expressed independently of each other in vivo.
“However, phenotypic markers that appear to be coregulated in cultured Mp can be expressed independently of each other in vivo.”
Quote in the paperNot a substantial claim - Interpretationnone given
Mp during the early stages of tissue repair exhibit a more proinflammatory phenotype than their later counterparts.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
- Interpretationreasoning
Mp present during tissue repair are not a single homogenous population but include a temporally regulated spectrum of activation states to orchestrate the various phases of healing.
“Mp present during tissue repair are not a single homogenous population but include a temporally regulated spectrum of activation states to orchestrate the various phases of healing.”
Quote in the paperSubstantial claim- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
- Interpretationreasoning
Nomination of M2a Mp as the primary Mp effectors of tissue repair is an oversimplification at best and likely not warranted.
“We argue below that nomination of M2a Mp as the primary Mp effectors of tissue repair is an oversimplification at best and likely not warranted.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Later-stage tissue-repair Mp may exhibit some M2a-associated characteristics.
“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.”
Quote in the paperNot a substantial claim- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
- Interpretationnone given
In vivo tissue-repair Mp at any time-point do not share sufficient similarities with in vitro-defined phenotypes to justify labeling them as wholly M1 or M2.
“However, we argue here that whereas Mp of the inflammatory phase do, in fact, seem to present a more proinflammatory phenotype than their later-phase counterparts, in vivo tissue-repair Mp at any time-point do not share sufficient similarities with in vitro-defined phenotypes to justify labeling them as wholly M1 or M2.”
Quote in the paperSubstantial claim- 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.
- Premisecitation
In freshly isolated human peritoneal Mp, cell-surface expression of CD206 or the M2c marker CD163 does not correlate with expression of the M2-associated genes TGF-β, CCL18, or matrix metalloproteinase 9.
“Additionally, in freshly isolated human peritoneal Mp, cell-surface expression of CD206 or the M2c marker CD163 does not correlate with expression of the M2-associated genes TGF-, CCL18, or matrix metalloproteinase 9 [53].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Bellón, 2011, Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis, Nephrol. Dial. Transplant. source
Not checked in the free run.
- Interpretationnone given
M1- and M2-associated markers may be expressed simultaneously by actual tissue-repair Mp.
“Additionally, M1-and M2-associated markers may be expressed simultaneously by actual tissue-repair Mp.”
Quote in the paperNot a substantial claim - Premisecitation
Genetic deletion of IL-4Rα greatly reduces mRNA expression of the M2a markers Ym1, FIZZ1, and arginase-1 in peritoneal exudate cells after peritoneal incisional wounding in mice.
“Genetic deletion of IL-4R␣ greatly reduces mRNA expression of the M2a markers Ym1, FIZZ1, and arginase-1 in peritoneal exudate cells (which include Mp, neutrophils, eosinophils, and lymphocytes) after peritoneal incisional wounding in mice [70], indicating that IL-4/-13 are important phenotypic regulators in this model.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Premisecitation
In mouse skeletal muscle injury by chemical toxin or unloading/reloading, IL-4 mRNA, although detectable, does not rise above uninjured levels over the course of healing.
“In mouse skeletal muscle injury by chemical toxin or unloading/reloading, IL-4 mRNA, although detectable, does not rise above uninjured levels over the course of healing [73,74].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [73] Deng, 2012, IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration, J. Immunol. source
Not checked in the free run.
- cites [74] Toschi, 2011, Skeletal muscle regeneration in mice is stimulated by local overexpression of V1a-vasopressin receptor, Mol. Endocrinol. source
Not checked in the free run.
- Interpretationreasoning
Even if particular M2a-associated cytokines are expressed by Mp during tissue repair, this does not guarantee that other aspects of the M2a phenotype are present.
“Thus, even if particular M2a-associated cytokines are expressed by Mp during tissue repair, this does not guarantee that other aspects of the M2a phenotype are present.”
Quote in the paperSubstantial claim - Premisecitation
In mouse skin wounds, IL-4 mRNA and protein are not detectable at early or late time-points.
“In mouse skin wounds, IL-4 mRNA and protein are not detectable at early or late time-points [60,71].”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
In mouse kidney ischemia-reperfusion injury, Mp expression of iNOS mRNA is highest at 1-day postinjury and subsequently declines.
“In mouse kidney ischemia-reperfusion injury, Mp expression of iNOS mRNA is highest at 1-day postinjury and subsequently declines, consistent with an early M1 phenotype [63].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] Lee, 2011, Distinct macrophage phenotypes contribute to kidney injury and repair, J. Am. Soc. Nephrol. source
Not checked in the free run.
- Premisecitation
Mp expression of mRNA and protein for these cytokines exhibits an early peak and subsequent decline after skin wounding or toxin-induced muscle injury in mice.
“Mp expression of mRNA and protein for these cytokines exhibits an early peak and subsequent decline after skin wounding [33,60] or toxin-induced muscle injury in mice [65], consistent with an early M1-like phenotype.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- cites [60] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine source
Not checked in the free run.
- cites [65] Perdiguero, 2011, p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair, J. Cell Biol. source
Not checked in the free run.
- Interpretationcitation
The importance of IL-4 and IL-13 as canonical M2a activators may vary across different situations of tissue repair.
“Although IL-4 and IL-13 are often assumed to induce a wound-healing phenotype in Mp, the importance of these canonical M2a activators may vary across different situations of tissue repair.”
Quote in the paperSubstantial claim - Premisecitation
Levels of IL-10 and TGF-β expression are not necessarily coregulated during tissue repair.
“Furthermore, levels of IL-10 and TGF- expression are not necessarily coregulated during tissue repair; Mp display increased mRNA expression of IL-10 but not TGF- during chronic liver fibrosis in mice, and deficiency of the chemokine receptor CX 3 CR 1 results in reduced IL-10 but increased TGF- expression by Mp [69].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] Aoyama, 2010, CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice, Hepatology source
Not checked in the free run.
- Interpretationreasoning
Expression of iNOS in rodent injury models appears to be highly context-dependent.
“In contrast to the fairly consistent up-regulation of proinflammatory cytokines by early tissue-repair Mp, expression of iNOS in rodent injury models appears to be highly context-dependent.”
Quote in the paperNot a substantial claim - Premisecitation
At 48 h after acute liver injury in mice, Mp express IL-10 simultaneously with TNF-α and IL-1β mRNA.
“For instance, at 48 h after acute liver injury in mice, Mp express IL-10 simultaneously with TNF-␣ and IL-1 mRNA [62].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [62] Karlmark, 2010, The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes, Hepatology source
Not checked in the free run.
- Premisecitation
CD206 expression is similar among TNF-α-high, -low, or -negative Mp.
“Additionally, CD206 expression is similar among TNF-␣-high, -low, or -negative Mp [33], which would not be expected if distinct M1 and M2a populations were present.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- Interpretationreasoning
The pattern of inflammatory cytokine production and iNOS expression suggests a proinflammatory but not entirely M1 Mp phenotype during the early stages of tissue repair.
“Taken together, the pattern of inflammatory cytokine production and iNOS expression suggests a proinflammatory but not entirely M1 Mp phenotype during the early stages of tissue repair.”
Quote in the paperSubstantial claim- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
- Premisecitation
After excisional skin wounding in rats or photochemical liver injury in mice, only a fraction of the wound Mp expresses iNOS (10-15% positive at peak in skin).
“After excisional skin wounding in rats [56] or photochemical liver injury in mice [68], only a fraction of the wound Mp expresses iNOS (10 -15% positive at peak in skin), and the heterogeneity of the Mp population may be dependent on proximity to the injured site [68].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [56] Miao, 2012, Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation, Wound Repair Regen. source
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- cites [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
Not checked in the free run.
- Premisecitation
During impaired muscle healing caused by loss of MAPK-phosphatase-1, peak Mp expression of TGF-β and IL-10 is shifted to earlier time-points and occurs simultaneously with peak proinflammatory cytokine expression.
“Interestingly, during impaired muscle healing caused by loss of MAPK-phosphatase-1 [65], peak Mp expression of TGF- and IL-10 is shifted to earlier time-points and occurs simultaneously with peak proinflammatory cytokine expression, contrary to expectations of an early-M1-tolate-M2 transition.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Perdiguero, 2011, p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair, J. Cell Biol. source
Not checked in the free run.
- Premisecitation
Mp in incisional mouse skin wounds appear to express iNOS only in response to invading pathogens and not as an inherent feature of the tissue-repair response.
“However, Mp in incisional mouse skin wounds appear to express iNOS only in response to invading pathogens and not as an inherent feature of the tissue-repair response [33,67].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
In mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair.
“Indeed, 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].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- cites [60] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine source
Not checked in the free run.
- cites [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 in the free run.
- cites [63] Lee, 2011, Distinct macrophage phenotypes contribute to kidney injury and repair, J. Am. Soc. Nephrol. source
Not checked in the free run.
- Interpretationcitation
Anti-inflammatory and proinflammatory cytokine expression may be induced simultaneously at early timepoints during tissue repair.
“Additionally, anti-inflammatory and proinflammatory cytokine expression may be induced simultaneously at early timepoints during tissue repair.”
Quote in the paperSubstantial claim - Interpretationnone given
Later macrophage populations may exhibit a more anti-inflammatory profile with increased expression of some M2a-associated markers, such as CD206.
“Similarly, whereas later Mp populations may exhibit a more anti-inflammatory profile with increased expression of some M2a-associated markers, such as CD206, others, such as Ym1, may be oppositely regulated, and the canonical M2a activators, IL-4 and IL-13, may or may not be present, depending on the tissue and mode of injury.”
Quote in the paperSubstantial claim - Interpretationnone given
Macrophages during the early stages of tissue repair seem to present a more generally proinflammatory profile than their later counterparts.
“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.”
Quote in the paperSubstantial claim - Premisereasoning
Tissue-repair macrophages are exposed to a vastly more complex microenvironment than macrophages treated with one or a few cytokines in a cell-culture dish.
“The plethora of factors that regulate Mp activation also complicate identification of Mp phenotypes in vivo; tissue-repair Mp are exposed to a vastly more complex microenvironment than Mp treated with one or a few cytokines in a cell-culture dish.”
Quote in the paperSubstantial claim - Interpretationreasoning
Markers used to define in vitro macrophage subsets may have no direct role in tissue injury and repair.
“attempts to sort tissue-repair Mp into discrete, in vitro -defined subsets that may not exist in vivo and are based on markers that may have no direct role in tissue injury and repair.”
Quote in the paperNot a substantial claim - Interpretationnone given
Discrete in vitro-defined macrophage subsets may not exist in vivo.
“attempts to sort tissue-repair Mp into discrete, in vitro -defined subsets that may not exist in vivo and are based on markers that may have no direct role in tissue injury and repair.”
Quote in the paperNot a substantial claim - Interpretationcitation
A comprehensive in vivo macrophage phenotype cannot be deduced solely from a limited set of phenotypic markers.
“Additionally, a comprehensive in vivo Mp phenotype cannot be deduced solely from a limited set of phenotypic markers, as different M2a-associated genes or proteins can exhibit entirely different temporal regulation and can be coexpressed with M1-associated markers [19,25,33,60,78].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [19] Stout, 2005, Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences, J. Immunol. source
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- cites [25] Menzies, 2010, Sequential expression of macrophage antimicrobial/inflammatory and wound healing markers following innate, alternative and classical activation, Clin. Exp. Immunol. source
Not checked in the free run.
- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- cites [60] Mirza, 2011, Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice, Cytokine source
Not checked in the free run.
- cites [78] Spencer, 2010, Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation, Am. J. Physiol. Endocrinol. Metab. source
Not checked in the free run.
- Premisecitation
Rodent and human macrophages do not exhibit entirely similar responses to in vitro activation.
“Finally and perhaps most importantly, rodent and human Mp do not exhibit entirely similar responses to in vitro activation [9,34,66,80], and it remains to be determined whether there are also species-dependent differences in Mp function during in vivo tissue repair.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [9] Mosser, 2008, Exploring the full spectrum of macrophage activation, Nat. Rev. Immunol. source
Not checked in the free run.
- cites [34] Brancato, 2011, Wound macrophages as key regulators of repair: origin, phenotype, and function, Am. J. Pathol. source
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- cites [66] Albina, 1995, On the expression of nitric oxide synthase by human macrophages. Why no NO?, J. Leukoc. Biol. source
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- cites [80] Raes, 2005, Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells, J. Immunol. source
Not checked in the free run.
- Interpretationreasoning
Macrophage plasticity likely contributes to the seemingly contradictory roles of macrophages in tissue injury, regeneration, and fibrosis.
“Different stimuli can produce a broad spectrum of functional Mp phenotypes, and this plasticity likely contributes to the seemingly contradictory roles of Mp in tis-sue injury, regeneration, and fibrosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Early-repair macrophages do not exhibit an entirely M1 phenotype.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
In vivo tissue-repair macrophages do not conform to existing, in vitro-defined phenotypic categories.
“Therefore, it is not surprising that in vivo tissue-repair Mp do not conform to existing, in vitro-defined phenotypic categories.”
- Also stated in: § CONCLUDING REMARKS · plain
“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.”
Quote in the paperSubstantial claim - Also stated in: § CONCLUDING REMARKS · plain
- Interpretationown data
Coexpression of M1- and M2a-associated markers precludes classification of early or late macrophages as purely M1 or M2a.
“the coexpression of M1-and M2a-associated markers precludes classification of early or late Mp as purely M1 or M2a (Table 1 and Fig. 1).”
Quote in the paperSubstantial claim - Premisenone given
Macrophages are critical orchestrators of repair and regeneration in numerous tissues.
“Mp are critical orchestrators of repair and regeneration in numerous tissues, but may also contribute to chronic tissue damage and fibrosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Whole-tissue content of cytokines or other markers of M2a activation is insufficient to determine the phenotype of macrophages during in vivo tissue repair.
“Whole-tissue content of cytokines or other markers of M2a activation is insufficient to determine the phenotype of Mp during in vivo tissue repair, as whole-tissue levels could be affected by expression in non-Mp cells or by changes in the number of Mp in the tissue.”
Quote in the paperSubstantial claim - Interpretationreasoning
Existing evidence is limited but does not support the notion that macrophages present during tissue repair are bona fide M2a macrophages.
“In summary, existing evidence is limited but does not support the notion that Mp present during tissue repair are bona fide M2a Mp.”
Quote in the paperSubstantial claim - Interpretationreasoning
Macrophages during the later stages of tissue repair are not entirely of the M2a phenotype.
“These data indicate that Mp during the later stages of tissue repair are not entirely of the M2a phenotype.”
Quote in the paperSubstantial claim - Premisenone given
Different stimuli can produce a broad spectrum of functional macrophage phenotypes.
“Different stimuli can produce a broad spectrum of functional Mp phenotypes, and this plasticity likely contributes to the seemingly contradictory roles of Mp in tis-sue injury, regeneration, and fibrosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
The plethora of factors that regulate macrophage activation complicates identification of macrophage phenotypes in vivo.
“The plethora of factors that regulate Mp activation also complicate identification of Mp phenotypes in vivo; tissue-repair Mp are exposed to a vastly more complex microenvironment than Mp treated with one or a few cytokines in a cell-culture dish.”
Quote in the paperSubstantial claim - Interpretationreasoning
The canonical M2a activators IL-4 and IL-13 may or may not be present during later tissue repair, depending on the tissue and mode of injury.
“Similarly, whereas later Mp populations may exhibit a more anti-inflammatory profile with increased expression of some M2a-associated markers, such as CD206, others, such as Ym1, may be oppositely regulated, and the canonical M2a activators, IL-4 and IL-13, may or may not be present, depending on the tissue and mode of injury.”
Quote in the paperSubstantial claim - Interpretationreasoning
Other M2a-associated markers, such as Ym1, may be oppositely regulated in later macrophage populations.
“Similarly, whereas later Mp populations may exhibit a more anti-inflammatory profile with increased expression of some M2a-associated markers, such as CD206, others, such as Ym1, may be oppositely regulated, and the canonical M2a activators, IL-4 and IL-13, may or may not be present, depending on the tissue and mode of injury.”
Quote in the paperSubstantial claim - Premisenone given
Macrophages may also contribute to chronic tissue damage and fibrosis.
“Mp are critical orchestrators of repair and regeneration in numerous tissues, but may also contribute to chronic tissue damage and fibrosis.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 5
- May combine two claims. 24
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAfter mouse skeletal muscle laceration, Mp expression of TGF-β mRNA and IL-10 mRNA appears to peak early, approximately 3 days postinjury.
“Similarly, after mouse skeletal muscle laceration, Mp expression of TGF- mRNA and IL-10 mRNA appears to peak early, ϳ3 days postinjury (unpublished results).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSkeletal muscle Mp express iNOS mRNA at 5 days after chemically induced injury but do not express iNOS at any time-point after laceration injury.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] Cheng, 2008, Endogenous interferon-γ is required for efficient skeletal muscle regeneration, Am. J. Physiol. Cell. Physiol. source
Not checked in the free run.
May combine two claims.
PremisecitationIn a mouse wound-healing model, Mp expression of the M2a marker CD206 does not require IL-4 or IL-13 and does not correlate with TNF-α production.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisenone givenTwo of the best-characterized in vitro Mp 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.
“two of the best-characterized in vitro phenotypes are a proinflammatory”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenM2a Mp express factors that are important for tissue repair.
“M2a Mp are frequently termed”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe M1 activator IFN-γ is up-regulated rapidly after injury to skeletal muscle and skin and is required for proper healing of these tissues.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55][56][57][58]
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningWound healing is 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenIn numerous physiological and pathological states, Mp exhibit extensive heterogeneity and plasticity.
“In numerous physiological and pathological states, Mp exhibit extensive heterogeneity and plasticity, and tissue repair is no exception.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningExisting 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The phases of tissue repair (inflammation, proliferation, remodeling) are universal across tissues.
May combine two claims.
PremisecitationIn a mouse sponge-implantation model of skin wounding, deletion of IL-4Rα has no effect on Mp phenotype, and IL-4 and IL-13 are not detected in wound cells or fluids at any time.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
May combine two claims.
PremisecitationDuring mouse skin wound healing, Mp expression of TGF-β mRNA and protein increases over the first 7-10 days postinjury, whereas proinflammatory cytokine production decreases.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAfter 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.
“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].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
May combine two claims.
PremisecitationSeven days after photochemical injury to the liver, CD206+ cells are observed near the border of the injured site, although these cells were not verified specifically as Mp, and no other time-points were examined.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
May combine two claims.
InterpretationreasoningM2a 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn murine skeletal muscle, Mp expression of TGF-β 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.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [65] Perdiguero, 2011, p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair, J. Cell Biol. source
Not checked in the free run.
May combine two claims.
InterpretationcitationMp during skin wound healing exhibit a heterogeneous and temporally regulated phenotype that does not conform strictly to M1/M2 categorization.
“Thus, Mp during skin wound healing exhibit a heterogeneous and temporally regulated phenotype that does not conform strictly to M1/M2 categorization [33].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
- 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.
May combine two claims.
PremisecitationAlthough CD206, Ym1, and dectin-1 are expressed by murine subcutaneous wound Mp at 1, 3, and 7 days postinjury, 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.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningMany studies in other tissues that reported M2a markers during tissue repair have not determined whether these markers are expressed by Mp or by other cell types, and conclusions drawn regarding Mp phenotype are therefore dubious.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationRobust expression of iNOS is a hallmark of M1 activation in rodent Mp, although iNOS activity in human Mp appears to be much lower or absent entirely.
“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].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [14] Mantovani, 2004, The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol. source
Not checked in the free run.
- cites [66] Albina, 1995, On the expression of nitric oxide synthase by human macrophages. Why no NO?, J. Leukoc. Biol. source
Not checked in the free run.
May combine two claims.
InterpretationcitationAs IL-4/-13 activation is not always required for up-regulation of IL-10 and TGF-β, the presence of other aspects of the M2a phenotype should not be inferred from cytokine expression alone.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Daley, 2010, The phenotype of murine wound macrophages, J. Leukoc. Biol. source
Not checked in the free run.
May combine two claims.
PremisecitationIL-4 gene expression is elevated from 1 to 7 days in rat skin wounds, and protein expression is elevated between 12 h and 10 days in human skin wounds.
“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].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [56] Miao, 2012, Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation, Wound Repair Regen. source
Not checked in the free run.
- cites [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 in the free run.
- cites [72] Fraccarollo, 2008, Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response, Hypertension source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTissue-repair macrophages exhibit complex and heterogeneous phenotypes that change throughout the repair process.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Premisenone givenMacrophages are known to promote tissue-repair functions such as wound debridement, cell proliferation, angiogenesis, and matrix remodeling.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone givenA proinflammatory-to-anti-inflammatory transition may occur in many situations, but it appears to be context-dependent.
“A proinflammatory-to-anti-inflammatory transition may indeed occur in many situations, although this appears to be context-dependent”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningEarly tissue-repair macrophages may lack iNOS expression or may express CD206, Ym1, and IL-10 in addition to proinflammatory cytokines.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenSurprisingly few studies have examined macrophage-specific expression of M2a-associated genes or proteins in vivo or performed quantitative comparisons of cytokine production by cultured M1/M2a macrophages versus in vivo tissue-repair macrophages.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenMany potential modulators of macrophage activation have been identified in vitro.
“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.”
Quote in the paperNot a substantial claim
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 classical model distinguishes two major macrophage polarization phenotypes, M1 and M2, which represent a continuum providing a balance between pro- and anti-inflammatory responses.
“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]
The Introduction identifies classically activated M1 and alternatively activated M2 macrophages, and ‘Evolving Mp Activation Paradigms’ describes them as reference points on a continuum. But that section says macrophages are not merely switched between pro- and anti-inflammatory states: they can adopt multiple phenotypes. The claimed balance achieved by alternating between M1 and M2 overstates the paper’s account. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRecent studies have shown that macrophage phenotypes change over the different phases of tissue repair and that the sequential appearance of these phenotypes may be required for efficient repair.
“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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βig-h3 supports keratinocyte adhesion, migration, and proliferation through α3β1 integrin
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Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy
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Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis
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Regeneration versus fibrosis in skeletal muscle
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Regulation of arginase isoforms I and II by IL-4 in cultured murine peritoneal macrophages
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Ym1 Is a Neutrophil Granule Protein That Crystallizes in p47 -deficient Mice
Harbord, M., Novelli, M. R., Cañas, B., Power, D., Davis, C., Godovac‐Zimmermann, J., Roes, J., & Segal, A. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110635200 · Cited by 91 · see citing works
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Cytokine gene expression in a murine wound healing model
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Modulating macrophage function with IgG immune complexes
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Modulating macrophage function with IgG immune complexes
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Mechanisms and modulation of macrophage activation.
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Arginase is a major pathway of L-arginine metabolism in nephritic glomeruli
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Bacterial colonization and the expression of inducible nitric oxide synthase in murine wounds
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Regulation of Nitric Oxide Synthesis in Wounds by IFN-γ Depends on TNF-α
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Microglial <scp>M1/M2</scp> polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070 · see citing works
“While the initial response of macrophages to injury has been known for some time, positive influences on tissue remodelling have been recognized more recently (Longbrake et al., 2007; Ruffell et al., 2009; Deng et al., 2012; Novak and Koh, 2013; Shechter and Schwartz, 2013; Shechter et al., 2013).”
BackgroundUnderstanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms
Rőszer, T. (2015) · Mediators of Inflammation · doi:10.1155/2015/816460 · Cited by 1,762 · see citing works
“In response to the stimulus they sense, macrophages are being activated, which allows them to combat the pathogens, exert an immunomodulatory role, and maintain tissue integrity [4, 8, 9].”
BackgroundKrzyszczyk, P., Schloss, R. S., Palmer, A. F., & Francois Berthiaume, B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00419 · Cited by 1,562 · see citing works
“In in vivo studies, this nomenclature is not as widely used to identify macrophages, potentially due to the heterogeneous populations present, which are generated from a variety of stimuli within wounds (Novak and Koh, 2013).”
BackgroundVascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair
Johnson, K. E., & Wilgus, T. A. (2014) · Advances in wound care · doi:10.1089/wound.2013.0517 · Cited by 1,037 · see citing works
Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing
Hesketh, M., Sahin, K. B., West, Z. E., & Murray, R. Z. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071545 · Cited by 852 · see citing works
“M2 cells have been divided into four discrete types—M2a, M2b, M2c and M2d—in vitro based on their function and key markers (Table 1) [12].”
BackgroundThe Biology of Regeneration Failure and Success After Spinal Cord Injury
Tran, A. P., Warren, P. M., & Silver, J. (2018) · Physiological Reviews · doi:10.1152/physrev.00017.2017 · Cited by 883 · see citing works
“Activated immune cells additionally contribute to neuronal and glial cell death by generating ROS through increased NADPH oxidase activity (132, 288).”
BackgroundFlow Cytometric Analysis of Macrophages and Dendritic Cell Subsets in the Mouse Lung
Misharin, A. V., Morales-Nebreda, L., Mutlu, G. M., Budinger, G. R. S., & Perlman, H. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0086ma · Cited by 838 · see citing works
Macrophage activation and its role in repair and pathology after spinal cord injury
Gensel, J. C., & Zhang, B. (2015) · Brain Research · doi:10.1016/j.brainres.2014.12.045 · Cited by 774 · see citing works
Promoting tissue regeneration by modulating the immune system
Julier, Z., Park, A. J., Briquez, P. S., & Martino, M. M. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.01.056 · Cited by 766 · see citing works
Titanium surface characteristics, including topography and wettability, alter macrophage activation
Hotchkiss, K. M., Reddy, G. B., Hyzy, S. L., Schwartz, Z., Boyan, B. D., & Olivares‐Navarrete, R. (2015) · Acta Biomaterialia · doi:10.1016/j.actbio.2015.12.003 · Cited by 686 · see citing works
“Macrophages are responsible for the initial immune response, inflammation, and maintaining tissue homeostasis [3, 8, 9].”
BackgroundSicco, C. L., Reverberi, D., Balbi, C., Ulivi, V., Principi, E., Pascucci, L., Becherini, P., Bosco, M. C., Varesio, L., Franzin, C., et al. (2017) · Stem Cells Translational Medicine · doi:10.1002/sctm.16-0363 · Cited by 560 · see citing works
Current Advances in Immunomodulatory Biomaterials for Bone Regeneration
Lee, J., Byun, H., Perikamana, S. K. M., Lee, S., & Shin, H. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201801106 · Cited by 457 · see citing works
Soft tissue wound healing around teeth and dental implants
Sculean, A., Gruber, R., & Bosshardt, D. D. (2014) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12206 · Cited by 439 · see citing works
Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds
Aitcheson, S. M., Frentiu, F. D., Hurn, S. E., Edwards, K. P., & Murray, R. Z. (2021) · Molecules · doi:10.3390/molecules26164917 · Cited by 445 · see citing works
“The macrophage phenotype is complex and there are thought to be at least four types of pro-reparative M2 macrophages, namely M2a, M2b, M2c, and M2d, classified based on markers and functions, but not all appear to play a role in the wound [43].”
BackgroundTailoring Materials for Modulation of Macrophage Fate
Li, J., Jiang, X., Li, H., Gelinsky, M., & Gu, Z. (2021) · Advanced Materials · doi:10.1002/adma.202004172 · Cited by 402 · see citing works
The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication
Pakshir, P., & Hinz, B. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.01.019 · Cited by 396 · see citing works
Thapa, R. K., Diep, D. B., & Tønnesen, H. H. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.12.025 · Cited by 378 · see citing works
De Micheli, A. J., Laurilliard, E. J., Heinke, C. L., Ravichandran, H., Fraczek, P., Soueid-Baumgarten, S., De Vlaminck, I., Elemento, O., & Cosgrove, B. D. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.067 · Cited by 373 · see citing works
Martin, K. E., & Garcı́a, A. J. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.03.038 · Cited by 375 · see citing works
Macrophage-Mediated Inflammation in Skin Wound Healing
Hassanshahi, A., Moradzad, M., Ghalamkari, S., Fadaei, M., Cowin, A. J., & Hassanshahi, M. (2022) · Cells · doi:10.3390/cells11192953 · Cited by 375 · see citing works
“Interestingly, macrophages secrete IL-10, which prevents extra invasion of macrophages [10].”
BackgroundPhenotypic transitions of macrophages orchestrate tissue repair.
Novak, M. L., & Koh, T. (2013) · American Journal of Pathology · doi:10.1016/j.ajpath.2013.06.034 · Cited by 332 · see citing works
“Despite the predominantly proinflammatory cytokine profile of monocytes/macrophages during the early inflammatory phase, these cells are not fully analogous to in vitroedefined M1 macrophages.(12,13) For instance, early mouse skin wound monocytes/macrophages express high levels of arginase-1 and Ym1,(22,45) which are…”
BackgroundSelf-citationA Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration
Wosczyna, M. N., & Rando, T. A. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.06.018 · Cited by 353 · see citing works
OsteoMacs: Key players around bone biomaterials
Miron, R. J., & Bosshardt, D. D. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.12.017 · Cited by 321 · see citing works
“IL-4 and IL-13 are two important cytokines for MNGC fusion and formation and are thought to be produced mainly by T lymphocytes [154].”
Mirza, R. E., Fang, M. M., Weinheimer-Haus, E. M., Ennis, W. J., & Koh, T. J. (2014) · Diabetes · doi:10.2337/db13-0927 · Cited by 319 · see citing works
“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).”
BackgroundSelf-citationSepsis-Associated Acute Kidney Injury
Manrique‐Caballero, C. L., Rio‐Pertuz, G. D., & Gómez, H. (2021) · Critical Care Clinics · doi:10.1016/j.ccc.2020.11.010 · Cited by 334 · see citing works
Macrophage-based therapeutic strategies in regenerative medicine
Spiller, K. L., & Koh, T. J. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.010 · Cited by 308 · see citing works
Self-citationCollins, K. H., Herzog, W., MacDonald, G. Z., Reimer, R. A., Rios, J. L., Smith, I. C. P., Zernicke, R. F., & Hart, D. A. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00112 · Cited by 311 · see citing works
“Generally speaking, macrophages are dichotomized into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes based on their activity during tissue repair processes (Novak and Koh, 2013).”
BackgroundLiu, W. X., Li, J., Cheng, M., Wang, Q., Yeung, K., Chu, P. K.-H., & Zhang, X. (2018) · Advanced Science · doi:10.1002/advs.201800749 · Cited by 301 · see citing works
Maller, O., Drain, A. P., Barrett, A. S., Borgquist, S., Ruffell, B., Zakharevich, I., Pham, T. T. M., Gruosso, T., Kuasne, H., Lakins, J. N., et al. (2020) · Nature Materials · doi:10.1038/s41563-020-00849-5 · Cited by 295 · see citing works
Diverse origins of the myofibroblast—implications for kidney fibrosis
Falke, L. L., Gholizadeh, S., Goldschmeding, R., Kok, R. J., & Nguyen, T. Q. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2014.246 · Cited by 297 · see citing works
Macrophage Related Chronic Inflammation in Non-Healing Wounds
Li, M., Hou, Q., Zhong, L., Zhao, Y., & Fu, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.681710 · Cited by 299 · see citing works
“with downregulated inflammatory factors and upregulated antiinflammatory cytokines, including TGF-b, IL-10, and growth factors, such as platelet-derived growth factors (PDGF), resistinlike molecule-a (Relma), epidermal growth factor, and vascular endothelial growth factor-a (Vegfa), that drive tissue repair (18, 20, 4…”
BackgroundTumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy
Cersosimo, F., Lonardi, S., Bernardini, G., Telfer, B., Mandelli, G. E., Santucci, A., Vermi, W., & Giurisato, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155207 · Cited by 280 · see citing works
“Activation of macrophages is usually initiated via responses to stimuli present in their immediate surrounding microenvironment [57,75,76].”
BackgroundBasis of bone metabolism around dental implants during osseointegration and peri‐implant bone loss
Ínsua, Á., Monje, A., Wang, H., & Miron, R. J. (2017) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36060 · Cited by 278 · see citing works
“During dental implant osseointegration, classical M1macrophages secrete a wide array of pro-inflammatory cytokines including TNF-alpha, IL-1Beta, IL-6, Il-12, MMP2, and MMP9 typically induced by IFN-g 1 lipopolysaccharides (LPS) or TNF-a (in vitro).(158,160) In contrast, M2macrophages are produced in response to IL-4…”
BackgroundRole of macrophages in peripheral nerve injury and repair
Chang, F., Wang, Y., Liu, P., Peng, J. C., Han, G., Ding, X., Wei, S., Gao, G., & Huang, K. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.253510 · Cited by 267 · see citing works
“M2a, M2b and M2c macrophages release anti-inflammatory cytokines, and increase cell proliferation and migration, tissue remodeling ( via release of Arginase and Ym1) and secretion of growth factors (Novak and Koh, 2013a, b).”
BackgroundJiang, G., Li, S., Yu, K., He, B., Hong, J., Xu, T., Meng, J., Ye, C., Chen, Y., Shi, Z., et al. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.04.010 · Cited by 263 · see citing works
Acute Inflammation in Tissue Healing
Soliman, A. M., & Barreda, D. R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010641 · Cited by 283 · see citing works
Macrophages: A review of their role in wound healing and their therapeutic use
Snyder, R. J., Lantis, J., Kirsner, R. S., Shah, V., Molyneaux, M., & Carter, M. J. (2016) · Wound Repair and Regeneration · doi:10.1111/wrr.12444 · Cited by 245 · see citing works
“The antimicrobial and antitumoral M1 phenotype is activated upon wound formation by inflammatory signals from IFN-c and TFN-a, or when pathogen-associated molecular patterns or endogenous danger signals, such as heat shock proteins, are recognized.(18,19,21,31,76) These macrophages release IL-12 and promote strong pro…”
BackgroundMacrophages provide a transient muscle stem cell niche via NAMPT secretion
Ratnayake, D., Nguyen, P. D., Rossello, F. J., Wimmer, V. C., Tan, J. L., Galvis, L. A., Julier, Z., Wood, A. J., Boudier, T., Isiaku, A. I., et al. (2021) · Nature · doi:10.1038/s41586-021-03199-7 · Cited by 227 · see citing works
Endocannabinoids drive the acquisition of an alternative phenotype in microglia
Mecha, M., Feliú, A., Carrillo-Salinas, F. J., Rueda-Zubiaurre, A., Ortega-Gutiérrez, S., de Sola, R. G., & Guaza, C. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.06.002 · Cited by 234 · see citing works
IL-33-dependent group 2 innate lymphoid cells promote cutaneous wound healing
Rak, G. D., Osborne, L., Siracusa, M., Kim, B. S., Wang, K., Bayat, A., Artis, D., & Volk, S. (2016) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.406 · Cited by 205 · see citing works
Wüthrich, M., Deepe, G. S., & Klein, B. S. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074958 · Cited by 225 · see citing works
The multicellular complexity of peripheral nerve regeneration
Cattin, A.-L., & Lloyd, A. C. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2016.04.005 · Cited by 220 · see citing works
Macrophage Differentiation in Normal and Accelerated Wound Healing
Kotwal, G. J., & Chien, S. (2017) · Results and problems in cell differentiation · doi:10.1007/978-3-319-54090-0_14 · Cited by 205 · see citing works
“The final remodeling phase involves collagen remodeling (Novak and Koh 2013).”
BackgroundZhang, M., Wang, X., Wang, Y., Niu, A., Wang, S., Zou, C., & Harris, R. C. (2016) · Kidney International · doi:10.1016/j.kint.2016.08.020 · Cited by 205 · see citing works
Role of Fibroblast Populations in Periodontal Wound Healing and Tissue Remodeling
Smith, P. C., Martínez, C., Martı́nez, J., & McCulloch, C. A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00270 · Cited by 203 · see citing works
“These cells are sequentially recruited into the wound at the beginning and end of the inflammatory phase, respectively (Novak and Koh, 2013).”
BackgroundFrom Inflammation to Current and Alternative Therapies Involved in Wound Healing
Serra, M. B., Barroso, W. A., da Silva, N. N., Silva, S. D. N., Borges, A. C. R., Abreu, I. C., & Borges, M. O. D. R. (2017) · International Journal of Inflammation · doi:10.1155/2017/3406215 · Cited by 202 · see citing works
“In contrast, cytokines, such as IL-4 and IL-13, lead to macrophages formation of the M2 subset, which regulate inflammation by expressing mediators as IL-1 receptor antagonist (IL-1R), IL1 type II receptor, transforming growth factor-β (TGF-β), vasopressin endothelial growth factor (VEGF), and insulinlike growth facto…”
Nanoparticle clearance is governed by Th1/Th2 immunity and strain background.
Jones, S. W., Roberts, R. A., Robbins, G., Perry, J. L., Kai, M. P., Chen, K., Bo, T., Napier, M., Ting, J., DeSimone, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66895 · Cited by 177 · see citing works
Cosín‐Roger, J., Ortiz‐Masiá, D., Calatayud, S., Hernández, C., Esplugues, J. V., & Barrachina, M. D. (2015) · Mucosal Immunology · doi:10.1038/mi.2015.123 · Cited by 193 · see citing works
“The early expression observed in iNOS and CD11c, as well as that of two hallmark indicators of M2 activation (ArgI and Ym1), suggests that macrophages in the inflammatory phase of intestinal repair adopt a combination of M1 and M2 phenotypes similar to that reported in other tissues.(15,16,43) At 4 days after TNBS, th…”
BackgroundResultCD301b+ Macrophages Are Essential for Effective Skin Wound Healing
Shook, B. A., Xiao, E.-C., Kumamoto, Y., Iwasaki, A., & Horsley, V. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.05.107 · Cited by 167 · see citing works
“The nature of the myeloid cell plasticity during tissue repair is not clear (Gordon and Taylor, 2005; Novak and Koh, 2013).”
Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury
Kabu, S., Gao, Y., Kwon, B. K., & Labhasetwar, V. D. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.060 · Cited by 188 · see citing works
Rethinking Regenerative Medicine: A Macrophage-Centered Approach
Brown, B., Sicari, B. M., & Badylak, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00510 · Cited by 185 · see citing works
“During the granulation tissue formation and wound contraction phase of cutaneous wound healing at 7–10 days post-injury, paracrine effector molecules, including cytokines such as IL-10 and growth factors such as VEGF, PDGF-β, and TGF-β, produced by M2 macrophages recruit fibroblasts into the wound site and promote myo…”
BackgroundInfluentialLi, J., Wen, J., Li, B., Wan, L., Qiao, W., Shen, J., Jin, W., Jiang, X., Yeung, K., & Chu, P. K.-H. (2017) · Advanced Science · doi:10.1002/advs.201700678 · Cited by 184 · see citing works
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“(A) The mRNA levels of macrophage M1 biomarkers (iNOS, IL-1b and IL-6) were examined by qRT-PCR.”
BackgroundInfluentialRetractedThe neuroimmunology of degeneration and regeneration in the peripheral nervous system
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“Regardless of the differing hypotheses concerning the macrophage activation state after nerve injury, it may be that macrophages involved in tissue repair encompass a spectrum of activation states throughout the repair process (for review see Novak and Koh, 2013).”
Peptides as Therapeutic Agents for Inflammatory-Related Diseases
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“NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA and plays a key role in inflammation; normally, it localizes in the cytoplasm, but under inflammatory conditions, it translocates into the nucleus where it regulates the pro-inflammatory gene…”
BackgroundMacrophages in the Aging Liver and Age-Related Liver Disease
Stahl, E. C., Haschak, M. J., Popovic, B., & Brown, B. N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02795 · Cited by 171 · see citing works
“M2-polarized macrophages typically appear following M1-polarized macrophages in an injury setting and serve as a counterbalance to resolve inflammation and promote tissue repair (34).”
BackgroundSaldaña, L., Bensiamar, F., Vallés, G., Mancebo, F. J., García‐Rey, E., & Vilaboa, N. E. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1156-6 · Cited by 172 · see citing works
Regulatory T cells in skin injury: At the crossroads of tolerance and tissue repair
Boothby, I. C., Cohen, J. N., & Rosenblum, M. D. (2020) · Science Immunology · doi:10.1126/sciimmunol.aaz9631 · Cited by 174 · see citing works
“IFN- activates macrophages toward an inflammatory phenotype analogous to classically activated (“M1”) macrophages described in vitro (64).”
BackgroundHuang, C., Wang, J., Liu, H., Huang, R., Yan, X., Song, M., Tan, G., & Zhi, F. (2022) · BMC Medicine · doi:10.1186/s12916-022-02352-x · Cited by 173 · see citing works
“TGFb enhances fibroblast proliferation and collagen production observed in macrophage/fibroblast co-cultures [46].”
BackgroundFunction of Macrophages in Disease: Current Understanding on Molecular Mechanisms
Zhang, C., Yang, M. J., & Ericsson, A. C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.620510 · Cited by 162 · see citing works
Harnessing Tissue-derived Extracellular Vesicles for Osteoarthritis Theranostics
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“On the other hand, several leukocyte subsets, including M2 macrophages showing anti-inflammatory may initiate tissue repair and suppress fibrosis [129].”
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“145, 146 Macrophages thus are positioned at the intersecting innate and adaptive immune responses continuously modulating the Th1 and Th2 cytokine balance during infection.”
BackgroundAmelioration of ulcerative colitis via inflammatory regulation by macrophage-biomimetic nanomedicine
Sun, T., Kwong, C. H. T., Cheng, G., Wei, J., Yue, L., Zhang, J., Ye, R. D., & Wang, R. (2020) · Theranostics · doi:10.7150/thno.48448 · Cited by 160 · see citing works
“M1 macrophages produce pro-inflammatory cytokines and ROS, whereas M2 macrophages secret anti-inflammatory cytokines, accelerate inflammation resolution and promote tissue repair [42, 43], thus M2 macrophage was previously leveraged for UC therapy [22].”
BackgroundEffects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis
Bickelhaupt, S., Erbel, C., Timke, C., Wirkner, U., Dadrich, M., Flechsig, P., Tietz, A., Pföhler, J., Groß, W., Peschke, P., et al. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw339 · Cited by 151 · see citing works
“by FG-3019 was reflected in the transcriptome by normalizing markers for mast cells and M2 polarized macrophages, but not M1 macrophages (Figure 5, B–D) (68,69).”
BackgroundM2 Macrophages as a Potential Target for Antiatherosclerosis Treatment
Bi, Y., Chen, J., Hu, F., Liu, J., Li, M., & Zhao, L. (2019) · Neural Plasticity · doi:10.1155/2019/6724903 · Cited by 153 · see citing works
“Researches show that the M2 phenotype could secrete anti-inflammatory factors [10], promote tissue remodeling and repair [11, 12], and clear dying cells and debris [13], thus contributing to atheroma therapy.”
BackgroundBai, J., Wang, H., Chen, H., Ge, G., Wang, M., Gao, A., Tong, L., Xu, Y., Yang, H., Pan, G., et al. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120197 · Cited by 153 · see citing works
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“sponse, the appropriate balance of these activation states is thought to be vital for optimal wound healing and could be harnessed to promote regeneration.(23,24) Graphical Abstract 1358 L.”
BackgroundReconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry
Notter, T., Coughlin, J. M., Sawa, A., & Meyer, U. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.232 · Cited by 142 · see citing works
Wound Chronicity, Impaired Immunity and Infection in Diabetic Patients
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“…polarize to an M2 subpopulation with anti-in fl ammatory activity by expressing interleukin-receptor antagonists and a collection of fi broangiogenic growth factors that enhance fi broblast proliferation, extracellular matrix synthesis, angiogenesis,[59,60] ultimately reducing in fl ammation .”
BackgroundMareninova, O. A., Sendler, M., Malla, S. R., Yakubov, I., French, S. W., Tokhtaeva, E., Vagin, O., Oorschot, V. M. J., Lüllmann‐Rauch, R., Blanz, J., et al. (2015) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2015.07.006 · Cited by 142 · see citing works
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“Monocytes and macrophages play a pivotal role in coordinating the various stages of the wound healing process by their ability to produce and secrete numerous growth factors, cytokines and other mediators capable of exerting paracrine effects on other cells in affected tissues [27,59-72,154-157].”
BackgroundMacrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases
Benedetto, P. D., Ruscitti, P., Vadasz, Z., Toubi, E., & Giacomelli, R. (2019) · Autoimmunity Reviews · doi:10.1016/j.autrev.2019.102369 · Cited by 139 · see citing works
Preparation and Use of Decellularized Extracellular Matrix for Tissue Engineering
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Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD
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“Induced by fungi, immunocomplexes, helminths, complement components, apoptotic cells, macrophage colony-stimulating factors, IL-4, and IL-13, M2 macrophages secrete anti-inflammatory cytokines, including IL-10, TGF-β, CCL18, and CCL22 [7], and are generally characterized by their high CD163 and CD206 expression levels…”
BackgroundMacrophage polarization states in atherosclerosis
Wu, J., He, S., Song, Z., Chen, S., Lin, X., Sun, H., Zhou, P., Peng, Q., Du, S., Zheng, S., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1185587 · Cited by 142 · see citing works
“Consequently, they are usually referred to as wound healing macrophages (29).”
BackgroundWang, J., Meng, F., Song, W., Jin, J., Ma, Q., Fei, D., Fang, L., Chen, L., Wang, Q., & Zhang, Y. (2018) · International Journal of Nanomedicine · doi:10.2147/ijn.s163956 · Cited by 137 · see citing works
“38 The wound and implant sites naturally contain a combination of stimuli that favor both M1 and M2 macrophage polarization at different stages of healing, 17,39 thus, from results of IHC staining, both iNOS-positive cells and CD163-positive cells could be found around the implants.”
Host response to synthetic mesh in women with mesh complications
Nolfi, A. L., Brown, B. N., Liang, R., Palcsey, S. L., Bonidie, M. J., Abramowitch, S. D., & Moalli, P. (2016) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2016.04.008 · Cited by 136 · see citing works
Regulation of decellularized matrix mediated immune response
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Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension
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Innate immunity activation in the early brain injury period following subarachnoid hemorrhage
on behalf of the Canadian Critical Care Translational Biology Group, Gris, T., Laplante, P., Thébault, P., Cayrol, R., Najjar, A. A., Joannette-Pilon, B., Brillant-Marquis, F., Magro, E., English, S. W., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1629-7 · Cited by 131 · see citing works
“These macrophages are reprogrammed in response to their microenvironment into several phenotypes ranging from pro-inflammatory to anti-inflammatory macrophages [40].”
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The role of macrophages in the formation of hypertrophic scars and keloids
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“The temporal changes in M1/M2 distribution occur in various tissue repair processes and fibrosis, including skin [30], kidney [31] and liver [32].”
BackgroundOsteoinduction and osteoimmunology: Emerging concepts
Miron, R. J., Bohner, M., Zhang, Y., & Bosshardt, D. D. (2023) · Periodontology 2000 · doi:10.1111/prd.12519 · Cited by 135 · see citing works
Attributes of alternatively activated (M2) macrophages
Shrivastava, R., & Shukla, N. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.03.062 · Cited by 130 · see citing works
Capote, J. C., Kramerova, I. A., Martinez, L., Vetrone, S. A., Barton, E. R., Sweeney, H. L., Miceli, M. C., & Spencer, M. J. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201510086 · Cited by 122 · see citing works
“JCB • Volume 213 • NumBer 2 • 2016 276 and reactive nitrogen and oxygen intermediates (Mantovani et al., 2007; Novak and Koh, 2013; Liu et al., 2014; Rigamonti et al., 2014).”
BackgroundThe role of macrophages during acute kidney injury: destruction and repair
Han, H. I., Skvarca, L. B., Espiritu, E. B., Davidson, A. J., & Hukriede, N. A. (2018) · Pediatric Nephrology · doi:10.1007/s00467-017-3883-1 · Cited by 121 · see citing works
“Upon activation, the recruited macrophages secrete inflammatory cytokines such as IL-1β, TNFα, IL-12, IL-18, and IL-23 [2] (Fig.”
IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice.
He, R., Yin, H., Yuan, B., Liu, T., Luo, L., Huang, P., Dai, L., & Zeng, K. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.06.249 · Cited by 111 · see citing works
“…in all stages of wound healing and orchestrate the wound repair process by exerting proinflammatory functions during the early stage and stimulating proliferation of fibroblasts, keratinocytes, and endothelial cells in the proliferative stage (Brancato and Albina, 2011; Novak and Koh, 2013).”
BackgroundThe M2a macrophage subset may be critically involved in the fibrogenesis of endometriosis in mice
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Macrophages in organ fibrosis: from pathogenesis to therapeutic targets
Jiang, Y., Cai, R., Huang, Y., Zhu, L., Xiao, L., Wang, C., & Wang, L. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02247-1 · Cited by 126 · see citing works
Extracellular traps and macrophages: new roles for the versatile phagocyte
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“[103–108]), it is not surprising that they are being included in”
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“It is described in the literature that about 85% of macrophages in the wounded tissue have an M1 pro-inflammatory phenotype in the early stages of repair, and a switch is observed by Days 5–7 to about 80–85% of anti-inflammatory M2 macrophages [37].”
BackgroundAdaptive Immunity to FungiPreprint
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Distinct inflammatory and wound healing responses to complex caudal fin injuries of larval zebrafish
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3D in vitro M2 macrophage model to mimic modulation of tissue repair
Sapudom, J., Karaman, S., Mohamed, W. K. E. A., Garcia‐Sabaté, A., Quartey, B. C., & Teo, J. C. M. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-021-00193-5 · Cited by 114 · see citing works
Giant cells around bone biomaterials: Osteoclasts or multi-nucleated giant cells?
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Temporal changes in macrophage phenotype after peripheral nerve injury
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“To further characterize the macrophage polarization pattern in this system, we performed immunohistochemical staining of arginase-1 and mannose receptor 1 (MR1) as markers of pro-fibrotic M2 macrophages [33,34].”
MethodEffect of Platelet-Rich Plasma on M1/M2 Macrophage Polarization
Uchiyama, R., Toyoda, E., Maehara, M., Wasai, S., Omura, H., Watanabe, M., & Sato, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052336 · Cited by 111 · see citing works
“and are essential for early tissue repair of damaged or inflamed areas [30,31].”
BackgroundBiomaterials strategies to balance inflammation and tenogenesis for tendon repair
Hou, J., Yang, R., Vuong, I., Li, F., Kong, J., & Mao, H. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.05.043 · Cited by 110 · see citing works
- 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 · 2012: 1
- 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 › Rehabilitation › 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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