The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling

Christopher James Ferrante, Grace Pinhal-Enfield, Genie Elson, Bruce Neil Cronstein, G. Haskó, Shalini Outram, Samuel Joseph Leibovich

Research output: Contribution to journalArticle

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Abstract

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 (A2AR) 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.

Original languageEnglish
Pages (from-to)921-931
Number of pages11
JournalInflammation
Volume36
Issue number4
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Interleukin-4 Receptor alpha Subunit
Adenosine
Macrophages
Phenotype
Interleukin-12
Interleukin-10
Cytokines
Arginase
Tumor Necrosis Factor-alpha
Toll-Like Receptors
Interferons
Vascular Endothelial Growth Factor A
Lipopolysaccharides
Adenosine A2 Receptor Agonists
Interleukin-4 Receptors
Interleukin-13
Endotoxins
Nitric Oxide Synthase
Interleukin-4

Keywords

  • adenosine receptor
  • alternative activation
  • IL-4Rα
  • macrophage
  • TLR

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. / Ferrante, Christopher James; Pinhal-Enfield, Grace; Elson, Genie; Cronstein, Bruce Neil; Haskó, G.; Outram, Shalini; Leibovich, Samuel Joseph.

In: Inflammation, Vol. 36, No. 4, 08.2013, p. 921-931.

Research output: Contribution to journalArticle

Ferrante, Christopher James ; Pinhal-Enfield, Grace ; Elson, Genie ; Cronstein, Bruce Neil ; Haskó, G. ; Outram, Shalini ; Leibovich, Samuel Joseph. / The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. In: Inflammation. 2013 ; Vol. 36, No. 4. pp. 921-931.
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