title: 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 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.
authors.affiliation: The Department of Cell Biology and Molecular Medicine, New Jersey Medical School, UMDNJ, 185 South Orange Avenue, Newark, NJ 07103, USA.
authors.forename: Christopher James
authors.initials: CJ
authors.lastname: Ferrante
authors.forename: Grace
authors.initials: G
authors.lastname: Pinhal-Enfield
authors.forename: Genie
authors.initials: G
authors.lastname: Elson
authors.forename: Bruce Neil
authors.initials: BN
authors.lastname: Cronstein
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Hasko
authors.forename: Shalini
authors.initials: S
authors.lastname: Outram
authors.forename: Samuel Joseph
authors.initials: SJ
authors.lastname: Leibovich
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis; D000099181:Dectin-1
chemical_list: D000241:Adenosine; D001119:Arginase; D036341:Intercellular Signaling Peptides and Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D053662:Interleukin-4 Receptor alpha Subunit; D037102:Lectins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D052247:Nitric Oxide Synthase Type II; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D001619:beta-N-Acetylhexosaminidases; D000099181:Dectin-1; C413576:Retnla protein, mouse; C467480:vascular endothelial growth factor A, mouse; C496317:Nos2 protein, mouse; C429541:Chil3 protein, mouse; C544448:Arg1 protein, mouse