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Inflammation

, Volume 36, Issue 4, pp 921–931 | Cite as

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
  • Gyorgy Hasko
  • Shalini Outram
  • Samuel Joseph LeibovichEmail author
Article

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.

KEY WORDS

macrophage alternative activation IL-4Rα adenosine receptor TLR 

Notes

ACKNOWLEDGMENTS

This study was supported by grants from the US Public Health Service (RO1-GM068636 to SJL and RO1-GM066189 to GH).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Christopher James Ferrante
    • 1
  • Grace Pinhal-Enfield
    • 1
  • Genie Elson
    • 1
  • Bruce Neil Cronstein
    • 3
  • Gyorgy Hasko
    • 2
  • Shalini Outram
    • 1
  • Samuel Joseph Leibovich
    • 1
    Email author
  1. 1.The Department of Cell Biology and Molecular MedicineNew Jersey Medical School, UMDNJNewarkUSA
  2. 2.Department of SurgeryNew Jersey Medical School, UMDNJNewarkUSA
  3. 3.Division of Translation Medicine, Department of MedicineNew York University School of MedicineNew YorkUSA

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