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Cited by 4,689Immune cells in cancerImmune Response and InflammationPhagocytosis and Immune Regulation

The M1 and M2 paradigm of macrophage activation: Time for reassessment

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Martinez, Fernando O., Gordon, Siamon·2014·F1000Prime Reports
DOI 10.12703/p6-13PMC PMC3944738
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Abstract

Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.

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  • M2 cells, alternatively activated by IL-4, IL-10, IL-13, TGF-β, and immune complexes, exhibit a more anti-inflammatory phenotype and promote fibrosis resolution.

    “Conversely, M2 cells, alternatively activated by IL-4, IL-10, IL-13, TGF-β, and immune complexes, exhibit a more anti-inflammatory phenotype and promote the fibrosis resolution [77].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [77]

    The “M2 stimuli” and “M1-M2 concept: background” sections identify IL-4, IL-13, IL-10, TGF-β, and immune-complex signaling in the M2 grouping and describe antagonism of inflammatory responses. Table 1 in “M1 and M2 in disease: lack of defined subsets” reports that Arg1-positive macrophages suppress Th2 inflammation and fibrosis, but it does not establish that M2 cells generally promote the resolution of existing fibrosis. The indexed passages provide section labels but no page numbers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Common cytokines used in biomaterial-based research include proinflammatory IFN-γ or IL-4, which are important effectors in steering macrophage phenotypes.

    “Some of the more common cytokines used in biomaterial‐based research involves the proinflammatory IFN‐γ or IL‐4, which are important effectors in steering the macrophage phenotypes.[ 103 , 232 , 233 , 234 ]”

    From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [233]

    The M1 stimuli section identifies IFN-γ as a principal cytokine associated with M1 activation, while the M2 stimuli section identifies IL-4 as an M2 stimulus. But that section says M2 stimuli antagonize inflammatory responses, contrary to describing IL-4 as proinflammatory. The cited passages also do not establish that either cytokine is commonly used in biomaterial-based research. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Marker expression regularly overlaps across activation states.

    “While specific markers have been considered to accompany activation status, whereby pro-inflammatory macrophages typically express high levels of CD86 and MHC-II, and reparative or anti-inflammatory macrophages often express CD163 and CD206 (107), marker expression regularly overlaps across activation states.”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [107]

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Cited by

Sorted by citations

Authors
Martinez, F. O., & Gordon, S.
Affiliations
University of Oxford (GB)
Corresponding author
Gordon, Siamon
ORCID
Gordon, Siamon
Venue
F1000Prime Reports
Publisher
H1 Connect
Published
2014-03-03
Volume
6
Pages
13-13
ISSN
2051-7599 (ISSN-L)
DOI
10.12703/p6-13
PMC
PMC3944738
OpenAlex
W2140380746
Cited by
4,689
References
11
Citations by year
2026: 192 · 2025: 268 · 2024: 348 · 2023: 373 · 2022: 476 · 2021: 498 · 2020: 518 · 2019: 525 · 2018: 458 · 2017: 417 · 2016: 312 · 2015: 231 · 2014: 60 · 2012: 1
FWCI
33.17
Type
journal article
Language
en
Open access
Locations
  • F1000Prime Reports (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Open Research (University of Surrey) (submittedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
macrophage activation, M1 macrophages, M2 macrophages, alternative activation, cytokines, immune receptors, macrophage heterogeneity

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