IRF5 promotes inflammatory macrophage polarization and T_H1-T_H17 responses

Krausgruber, T. et al. Nat. Immunol. 12, 231-239 (2011).

Speaker: Fu-I Tsai (蔡馥儀)                                  Time: 15:10~16:00, Oct. 19, 2011

Commentator: Dr. Pin Ling (凌 斌 老師)           Place: Room 601

Abstract:

In response to ectopic stimuli, macrophages which differentiate to M1 (classically activated) macrophages demonstrate an IL-12^hiIL-23^hiIL-10^lo cytokine profile while M2 (alternatively activated) macrophages display an IL-12^loIL-23^loIL-10^hi cytokine profile. Previous study showed that IRF5 deficient mice lead to less production of IL-12p40 and IL-23p19^1,2, which are universal markers of M1 macrophages. Hence, the specific aim of this study is to investigate whether IRF5 is involved in macrophage polarization. To examine the expression of IRF5 in M1 and M2 macrophage, granulocyte-macrophage colony stimulating factor (GM-CSF) or interferon-γ (IFN-γ) were used to induce M1 phenotype from human monocytes, and macrophage colony stimulating factor (M-CSF) was used to induce M2 phenotype. They found that the mRNA and protein levels of IRF5 were higher in M1 macrophages than in M2 macrophages. Moreover, treatment of M-CSF in M1 macrophages decreased IRF5 expression, and treatment of GM-CSF in M2 macrophages increased IRF5 expression. Overexpression of IRF5 in M2 increased IL-12p70, IL-23 and IL-12p40 expression and downregulated IL-10 in both mRNA and protein level, whereas knockdown of IRF5 in M1 resulted in less IL-12p70, IL-23, IL-12p40 and more IL-10. In addition, results of T lymphocytes cultured with M2 macrophage infected with adenoviral vector encoding IRF5, shown to promote T_H1 and T_H17 responses. In keeping with these data, genome-wide expression analysis showed that IRF5 induced M1-specific and repressed M2-specific gene expression. Further experiments investigated that IRF5 bind to promoter regions of the genes encoding IL-12p40, IL-12p35, IL-23p19 and IL-10, which were consistent with RNA polymerase II recruitment. In conclusion, this study suggested that IRF5 is a subset-defining factor for M1 macrophages with both activating and repressive transcription functions.

References:

1. Ouyang, X. et al. Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem. Biophys. Res. Commun. 354, 1045–1051 (2007).

2. Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005).