GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling

J Leukoc Biol. 2009 Aug;86(2):411-21. doi: 10.1189/jlb.1108702. Epub 2009 Apr 30.


M-CSF and GM-CSF are mediators involved in regulating the numbers and function of macrophage lineage populations and have been shown to contribute to macrophage heterogeneity. Type I IFN is an important mediator produced by macrophages and can have profound regulatory effects on their properties. In this study, we compared bone marrow-derived macrophages (BMM) and GM-CSF-induced BMM (GM-BMM) from wild-type and IFNAR1(-/-) mice to assess the contribution of endogenous type I IFN to the phenotypic differences between BMM and GM-BMM. BMM were capable of higher constitutive IFN-beta production, which contributed significantly to their basal transcriptome. Microarray analysis found that of the endogenous type I IFN-regulated genes specific to either BMM or GM-BMM, 488 of these gene alterations were unique to BMM, while only 50 were unique to GM-BMM. Moreover, BMM displayed enhanced basal mRNA levels, relative to GM-BMM, of a number of genes identified as being dependent on type I IFN signaling, including Stat1, Stat2, Irf7, Ccl5, Ccl12, and Cxcl10. As a result of prior type I IFN "priming," upon LPS stimulation BMM displayed increased activation of the MyD88-independent IRF-3/STAT1 pathways compared with GM-BMM, which correlated with the distinct cytokine/chemokine profiles of the two macrophage subsets. Furthermore, the autocrine type I IFN signaling loop regulated the production of the M1 and M2 signature cytokines, IL-12p70 and IL-10. Collectively, these findings demonstrate that constitutive and LPS-induced type I IFN play significant roles in regulating the differences in phenotype and function between BMM and GM-BMM.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / drug effects
  • Autocrine Communication / immunology
  • Cell Lineage
  • Cells, Cultured
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Interferon Regulatory Factor-3 / drug effects
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / drug effects*
  • Interferon Type I / metabolism
  • Interferon-beta / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Receptors, Chemokine / drug effects
  • Receptors, Chemokine / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism


  • Cytokines
  • Ifnar1 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • RNA, Messenger
  • Receptors, Chemokine
  • Transcription Factors
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor