IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNγ

PLoS One. 2013;8(2):e56045. doi: 10.1371/journal.pone.0056045. Epub 2013 Feb 8.

Abstract

IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (Mφ) or dendritic cells (DC). A wide spectrum of Mφ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) Mφ (IL-34-Mφ). Upon LPS stimulation, IL-34-Mφ exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-Mφ exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-Mφ are phenotypically and functionally similar to M-CSF-Mφ. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive Mφ. Moreover, the generation of IL-34-Mφ is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFNγ and GM-CSF prevent the generation of immunosuppressive Mφ induced by IL-34. IFNγ also switches established IL-34-Mφ into immunostimulatory Mφ. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFNγ and GM-CSF prevent this effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects*
  • Cell Differentiation / immunology
  • Chemokines / genetics
  • Cluster Analysis
  • Gene Expression Profiling
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / biosynthesis
  • Interleukin-12 / biosynthesis
  • Interleukins / pharmacology*
  • Macrophages / cytology*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Monocytes / cytology*
  • Monocytes / drug effects*
  • Monocytes / immunology
  • Phenotype
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Receptors, Chemokine / genetics

Substances

  • Chemokines
  • Interleukins
  • Receptors, Chemokine
  • interleukin-34, human
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor

Grant support

This work was supported by institutional grants from INSERM (Institut national de la santé et de la recherche médicale) and the University of Angers and by a grant from La ligue contre le Cancer (Equipe labellisée 2012–2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.