The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling

J Leukoc Biol. 2015 Sep;98(3):395-407. doi: 10.1189/jlb.2A1114-560R. Epub 2015 Jun 5.


Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified 3 transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with TLR ligands in the presence of 3 different "reprogramming" signals: high-density ICs, PGE2, or Ado. All 3 of these cell populations produced high levels of transcripts for IL-10 and growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1β, IL-6, and IL-12. All 3 macrophage phenotypes could partially rescue mice from lethal endotoxemia, and therefore, we consider each to have anti-inflammatory activity. This ability to regulate innate-immune responses occurred equally well in macrophages from STAT6-deficient mice. The lack of STAT6 did not affect the ability of macrophages to change cytokine production reciprocally or to rescue mice from lethal endotoxemia. Furthermore, treatment of macrophages with IL-4 failed to induce similar phenotypic or transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These anti-inflammatory macrophages are transcriptionally and functionally related to each other and are quite distinct from macrophages treated with IL-4.

Keywords: RNA-seq; alternatively activated; endotoxemia; regulatory; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / metabolism*
  • Biomarkers / metabolism
  • Chemokines / metabolism
  • Female
  • Gene Expression Profiling
  • Glucose / metabolism
  • Humans
  • Immunomodulation / drug effects
  • Interleukin-4 / pharmacology
  • Lactic Acid / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation / drug effects
  • Macrophages / metabolism*
  • Metabolic Networks and Pathways / drug effects
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phenotype
  • STAT6 Transcription Factor / deficiency
  • STAT6 Transcription Factor / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction / drug effects


  • Anti-Inflammatory Agents
  • Biomarkers
  • Chemokines
  • Lipopolysaccharides
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4
  • Lactic Acid
  • Glucose