The Adenosine-Dependent Angiogenic Switch of Macrophages to an M2-Like Phenotype is Independent of Interleukin-4 Receptor Alpha (IL-4Rα) Signaling

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 suc...

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Published in:	Inflammation Vol. 36; no. 4; pp. 921 - 931
Main Authors:	Ferrante, Christopher James, Pinhal-Enfield, Grace, Elson, Genie, Cronstein, Bruce Neil, Hasko, Gyorgy, Outram, Shalini, Leibovich, Samuel Joseph
Format:	Journal Article
Language:	English
Published:	Boston Springer US 01-08-2013 Springer Nature B.V
Subjects:	Adenosine - metabolism Adenosine - pharmacology Animals Arginase - biosynthesis beta-N-Acetylhexosaminidases - biosynthesis Biomedical and Life Sciences Biomedicine Cell Differentiation Cells, Cultured Immunology Intercellular Signaling Peptides and Proteins - biosynthesis Interleukin-10 - biosynthesis Interleukin-12 - biosynthesis Interleukin-4 Receptor alpha Subunit - genetics Interleukin-4 Receptor alpha Subunit - metabolism Internal Medicine Lectins - biosynthesis Lectins, C-Type - biosynthesis Macrophage Activation Macrophages - drug effects Macrophages - immunology Male Mannose-Binding Lectins - biosynthesis Mice Mice, Inbred BALB C Mice, Transgenic Neovascularization, Physiologic - immunology Nitric Oxide Synthase Type II - biosynthesis Pathology Pharmacology/Toxicology Purinergic P1 Receptor Agonists - pharmacology Receptor, Adenosine A2A - metabolism Receptors, Cell Surface - biosynthesis Rheumatology Signal Transduction Tumor Necrosis Factor-alpha - biosynthesis Vascular Endothelial Growth Factor A - biosynthesis adenosine receptor macrophage alternative activation TLR IL-4Rα
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Summary:	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 A 2A 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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ISSN:	0360-3997 1573-2576
DOI:	10.1007/s10753-013-9621-3