IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses


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.


  1. 1

    Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Romagnani, P., Annunziato, F., Piccinni, M.P., Maggi, E. & Romagnani, S. TH1/TH2 cells, their associated molecules and role in pathophysiology. Eur. Cytokine Netw. 11, 510–511 (2000).

    CAS  PubMed  Google Scholar 

  5. 5

    Martinez, F.O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and TH17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Tamura, T. et al. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J. Immunol. 174, 2573–2581 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Porta, C. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc. Natl. Acad. Sci. USA 106, 14978–14983 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Ruffell, D. et al. A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. USA 106, 17475–17480 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Mancl, M.E. et al. Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. J. Biol. Chem. 280, 21078–21090 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Dideberg, V. et al. An insertion-deletion polymorphism in the interferon regulatory factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum. Mol. Genet. 16, 3008–3016 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Dieguez-Gonzalez, R. et al. Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis. Arthritis Rheum. 58, 1264–1274 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Graham, R.R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38, 550–555 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Kristjansdottir, G. et al. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations. J. Med. Genet. 45, 362–369 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Miceli-Richard, C. et al. Association of an IRF5 gene functional polymorphism with Sjogren's syndrome. Arthritis Rheum. 56, 3989–3994 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Fleetwood, A.J., Lawrence, T., Hamilton, J.A. & Cook, A.D. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J. Immunol. 178, 5245–5252 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Hoeve, M.A. et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur. J. Immunol. 36, 661–670 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Verreck, F.A., de Boer, T., Langenberg, D.M., van der Zanden, L. & Ottenhoff, T.H. Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-γ- and CD40L-mediated costimulation. J. Leukoc. Biol. 79, 285–293 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Krausgruber, T. et al. IRF5 is required for late-phase TNF secretion by human dendritic cells. Blood 115, 4421–4430 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Hammer, M. et al. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J. Exp. Med. 203, 15–20 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Fleetwood, A.J., Dinh, H., Cook, A.D., Hertzog, P.J. & Hamilton, J.A. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J. Leukoc. Biol. 86, 411–421 (2009).

    CAS  Article  Google Scholar 

  25. 25

    Ahern, P.P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Nistala, K. et al. TH17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc. Natl. Acad. Sci. USA 107, 14751–14756 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Martinez, F.O., Gordon, S., Locati, M. & Mantovani, A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Ziegler-Heitbrock, L. et al. IFN-α induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol. 171, 285–290 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Hamilton, J.A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    CAS  Article  Google Scholar 

  32. 32

    Negishi, H. et al. Negative regulation of Toll-like-receptor signaling by IRF-4. Proc. Natl. Acad. Sci. USA 102, 15989–15994 (2005).

    CAS  Article  Google Scholar 

  33. 33

    El Chartouni, C., Schwarzfischer, L. & Rehli, M. Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming. Immunobiology 215, 821–825 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Sanjabi, S., Hoffmann, A., Liou, H.C., Baltimore, D. & Smale, S.T. Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proc. Natl. Acad. Sci. USA 97, 12705–12710 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Mise-Omata, S. et al. A proximal κB site in the IL-23 p19 promoter is responsible for RelA- and c-Rel-dependent transcription. J. Immunol. 179, 6596–6603 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Fiorentino, D.F., Zlotnik, A., Mosmann, T.R., Howard, M. & O'Garra, A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 147, 3815–3822 (1991).

    CAS  Google Scholar 

  38. 38

    Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7–13 (2010).

    CAS  Article  Google Scholar 

  39. 39

    Mosser, D.M. & Zhang, X. Interleukin-10: new perspectives on an old cytokine. Immunol. Rev. 226, 205–218 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Schneemann, M. & Schoeden, G. Macrophage biology and immunology: man is not a mouse. J. Leukoc. Biol. 81, 579 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Ponting, C.P. The functional repertoires of metazoan genomes. Nat. Rev. Genet. 9, 689–698 (2008).

    CAS  Article  Google Scholar 

  42. 42

    Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Romagnani, S., Maggi, E., Liotta, F., Cosmi, L. & Annunziato, F. Properties and origin of human TH17 cells. Mol. Immunol. 47, 3–7 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Shen, H. et al. Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity. J Mol Cell Biol 2, 284–290 (2010).

    CAS  Article  Google Scholar 

  47. 47

    Campbell, I.K. et al. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J. Immunol. 161, 3639–3644 (1998).

    CAS  PubMed  Google Scholar 

  48. 48

    Cook, A.D., Braine, E.L., Campbell, I.K., Rich, M.J. & Hamilton, J.A. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 3, 293–298 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Lacaze, P. et al. Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling. BMC Genomics 10, 372 (2009).

    Article  Google Scholar 

  50. 50

    Liu, J., Cao, S., Herman, L.M. & Ma, X. Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-γ-primed IL-12 production by IFN regulatory factor 1. J. Exp. Med. 198, 1265–1276 (2003).

    CAS  Article  Google Scholar 

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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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The authors declare no competing financial interests.

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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).

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