IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses

Abstract

Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

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Figure 1: High expression of IRF5 in M1 macrophages and upregulation by GM-CSF.
Figure 2: IRF5 influences the production of macrophage lineage–specific cytokines.
Figure 3: IRF5 promotes lymphocyte proliferation and TH1-TH17 responses.
Figure 4: IRF5 regulates the expression of mRNA for macrophage lineage–specific cytokines.
Figure 5: IRF5 is directly involved in the transcriptional regulation of lineage-specific cytokines.
Figure 6: IRF5 inhibits the transcriptional activation of human IL10.
Figure 7: Impaired production of M1 and TH1-TH17 cytokines in Irf5−/− mice.

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Acknowledgements

We thank M. Cavanach for assistance with cell-characterization experiments; D. Barban for microarray hybridizations; F.G. Goh, D.G. Saliba and S. Thomson for advice and suggestions on RNA-mediated interference and chromatin immunoprecipitation; X. Ma (Cornell University) for luciferase constructs driven by the IL12A promoter; and C. Monaco and M.E. Goddard for support with animal experiments. Supported by the Medical Research Council (82189 to I.A.U.), the European Community Seventh Framework Programme FP7/2007-2013 (222008) and Arthritis Research UK.

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T.K., T.S., K.B. and S.A. did research; T.K., H.L., N.S. and I.A.U. designed research and analyzed data; and T.K., M.F., T.H. and I.A.U. wrote the paper.

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Correspondence to Irina A Udalova.

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Krausgruber, T., Blazek, K., Smallie, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 12, 231–238 (2011). https://doi.org/10.1038/ni.1990

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