The Adenosine-Dependent Angiogenic Switch of Macrophages to an M2-Like Phenotype is Independent of Interleukin-4 Receptor Alpha (IL-4Rα) Signaling
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Murine macrophages are activated by interferon-γ (IFN-γ) and/or Toll-like receptor (TLR) agonists such as bacterial endotoxin (lipopolysaccharide [LPS]) to express an inflammatory (M1) phenotype characterized by the expression of nitric oxide synthase-2 (iNOS) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-12. In contrast, Th2 cytokines IL-4 and IL-13 activate macrophages by inducing the expression of arginase-1 and the anti-inflammatory cytokine IL-10 in an IL-4 receptor-α (IL-4Rα)-dependent manner. Macrophages activated in this way are designated as "alternatively activated" (M2a) macrophages. We have shown previously that adenosine A2A receptor (A(2A)R) agonists act synergistically with TLR2, TLR4, TLR7, and TLR9 agonists to switch macrophages into an "M2-like" phenotype that we have termed "M2d." Adenosine signaling suppresses the TLR-dependent expression of TNF-α, IL-12, IFN-γ, and several other inflammatory cytokines by macrophages and induces the expression of vascular endothelial growth factor (VEGF) and IL-10. We show here using mice lacking a functional IL-4Rα gene (IL-4Rα(-/-) mice) that this adenosine-mediated switch does not require IL-4Rα-dependent signaling. M2d macrophages express high levels of VEGF, IL-10, and iNOS, low levels of TNF-α and IL-12, and mildly elevated levels of arginase-1. In contrast, M2d macrophages do not express Ym1, Fizz1 (RELM-α), or CD206 at levels greater than those induced by LPS, and dectin-1 expression is suppressed. The use of these markers in vivo to identify "M2" macrophages thus provides an incomplete picture of macrophage functional status and should be viewed with caution.
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Multiple pathways induce M2 and M2-like macrophages, including IL-4/IL-13-dependent signaling, TLR and IL-1R signaling with adenosine A(2A)R, CCL18, and CX3CL1.
“Recent studies suggest multiple pathways by which macrophages are induced to develop into M2 and M2-like macrophages. One pathway occurs through an IL-4/IL-13–dependent signaling cascade,95 a second is mediated through TLR and IL-1R signaling and adenosine-sensing receptor A(2A)R,56,95,96 a third is mediated by CCL18,97 and a fourth involves CX3CL1 (fractalkine).57”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [95]
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- Authors
- Ferrante, C. J., Pinhal-Enfield, G., Elson, G., Cronstein, B. N., Hasko, G., Outram, S., & Leibovich, S. J.
- Affiliations
- Rutgers New Jersey Medical School (US)
- New York University (US)
- Corresponding author
- Leibovich, Samuel Joseph
- Venue
- Inflammation
- Published
- 2013-03-17
- Volume
- 36
- Issue
- 4
- Pages
- 921-931
- ISSN
- 0360-3997 (ISSN-L)
- 1573-2576
- PMC
- PMC3710311
- OpenAlex
- W1998752508
- Cited by
- 375
- References
- 41
- Citations by year
- 2026: 20 · 2025: 42 · 2024: 43 · 2023: 51 · 2022: 42 · 2021: 37 · 2020: 32 · 2019: 25 · 2018: 25 · 2017: 17 · 2016: 18 · 2015: 11 · 2014: 11 · 2013: 1
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Inflammation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM068636, R01GM066189)
- National Institute of Allergy and Infectious Diseases (R21AI097731)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- adenosine, adenosine A2A receptor, macrophage polarization, M2 macrophages, IL-4 receptor alpha, Toll-like receptor signaling, vascular endothelial growth factor, IL-10, arginase-1, inducible nitric oxide synthase, Th2 cytokines, macrophage markers, Dectin-1, lipopolysaccharide
- MeSH terms
- Mannose Receptor, Dectin-1, Adenosine, Animals, Arginase, beta-N-Acetylhexosaminidases, Cell Differentiation, Cells, Cultured, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Mice, Transgenic, Receptors, Cell Surface, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-10, Interleukin-12, Neovascularization, Physiologic, Intercellular Signaling Peptides and Proteins, Lectins, Lectins, C-Type, Mannose-Binding Lectins, Vascular Endothelial Growth Factor A, Receptor, Adenosine A2A, Mice, Nitric Oxide Synthase Type II, Interleukin-4 Receptor alpha Subunit, Purinergic P1 Receptor Agonists
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