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Nature Reviews Immunology
  • Review Article
  • Published:

Transcriptional regulation of macrophage polarization: enabling diversity with identity

Nature Reviews Immunologyvolume 11, pages750–761 (2011)Cite this article

Subjects

Key Points

  • The macrophage lineage includes a remarkable variety of cells with different functions and functional states that are specified by the complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity.

  • The global regulatory landscape of macrophage-specific genes is controlled by the ETS family transcription factor PU.1, which dictates the general context in which sequence-specific transcription factors that are regulated by external stimuli operate to modulate macrophage phenotype and function.

  • Different sequence-specific transcription factors regulate macrophage polarization in specific contexts. Signal transducer and activator of transcription (STAT) proteins are pivotal factors in M1 and M2 macrophage polarization in response to T cell-derived cytokines; peroxisome proliferator-activated receptor-γ regulates the M2-like phenotype of macrophages in adipose tissue; and CCAAT/enhancer-binding protein-β activation mediated by cAMP-responsive element-binding protein drives the induction of M2 macrophages in muscle injury.

  • The polarized phenotype of macrophages is reinforced by the mutual exclusivity of signalling pathways and reciprocal regulation of M1 and M2 genes.

  • Tumour-associated macrophages (TAMs) are a unique polarized macrophage population characterized by the expression of both M1 and M2 marker genes. The specific transcriptional mechanisms that regulate the TAM phenotype remain poorly defined.

Abstract

In terms of both phenotype and function, macrophages have remarkable heterogeneity, which reflects the specialization of tissue-resident macrophages in microenvironments as different as liver, brain and bone. Also, marked changes in the activity and gene expression programmes of macrophages can occur when they come into contact with invading microorganisms or injured tissues. Therefore, the macrophage lineage includes a remarkable diversity of cells with different functions and functional states that are specified by a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity. In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease.

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Figure 1: The mononuclear phagocyte system.
Figure 2: Transcriptional control of macrophage identity and polarization.
Figure 3: Macrophage polarization in physiology and disease.
Figure 4: Mutual exclusivity and feed-forward signalling maintain macrophage polarization states.
Figure 5: Signal transduction pathways to M1 and M2 macrophage polarization.

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References

  1. Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu. Rev. Immunol.27, 669–692 (2009).

    Article CAS PubMed  Google Scholar 

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

    Article CAS  Google Scholar 

  3. Cheong, C. et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas.Cell143, 416–429 (2010).This paper established that monocyte-derived DCs, rather than non-myeloid DCs, are required for CD4+ and CD8+ T cell priming in the context of inflammation.

    Article CAS PubMed PubMed Central  Google Scholar 

  4. Sallusto, F. & Lanzavecchia, A. Monocytes join the dendritic cell family.Cell143, 339–340 (2010).

    Article CAS PubMed  Google Scholar 

  5. Gordon, S. The macrophage: past, present and future.Eur. J. Immunol.37, S9–S17 (2007).

    Article CAS PubMed  Google Scholar 

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

    Article CAS  Google Scholar 

  7. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages.Nature Immunol.3, 392–398 (2002).

    Article CAS  Google Scholar 

  8. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.Cell124, 263–266 (2006).

    Article CAS PubMed  Google Scholar 

  9. 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).This study is one of only a few to look at the transcriptome of human polarized macrophage subsets.

    Article CAS PubMed  Google Scholar 

  10. Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation).Blood107, 2112–2122 (2006).This was the first description of the specific transcriptional profile of TAMs.

    Article CAS PubMed  Google Scholar 

  11. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications.Nature447, 972–978 (2007).

    Article CAS PubMed  Google Scholar 

  12. Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance.Trends Immunol.30, 475–487 (2009).

    Article CAS PubMed  Google Scholar 

  13. Rosenbauer, F. & Tenen, D. G. Transcription factors in myeloid development: balancing differentiation with transformation.Nature Rev. Immunol.7, 105–117 (2007).

    Article CAS  Google Scholar 

  14. Olson, M. C. et al. PU.1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation.Immunity3, 703–714 (1995).

    Article CAS PubMed  Google Scholar 

  15. Nerlov, C. & Graf, T. PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors.Genes Dev.12, 2403–2412 (1998).References 14 and 15 demonstrated the essential role of PU.1 in the control of macrophage differentiation.

    Article CAS PubMed PubMed Central  Google Scholar 

  16. DeKoter, R. P. & Singh, H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1.Science288, 1439–1441 (2000).

    Article CAS PubMed  Google Scholar 

  17. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.Cell133, 1106–1117 (2008).

    Article CAS PubMed  Google Scholar 

  18. Tijssen, M. R. et al. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators.Dev. Cell20, 597–609 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  19. Siersbaek, R. et al. Extensive chromatin remodelling and establishment of transcription factor 'hotspots' during early adipogenesis.EMBO J.30, 1459–1472 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  20. Heintzman, N. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.Nature Genet.39, 311–318 (2007).This was the first paper to show the distinctive chromatin features of enhancers using high-throughput approaches.

    Article CAS PubMed  Google Scholar 

  21. Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression.Nature459, 108–112 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  22. Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state.Proc. Natl Acad. Sci. USA107, 21931–21936 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  23. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans.Nature470, 279–283 (2011).

    Article CAS PubMed  Google Scholar 

  24. Boyle, A. P. et al. High-resolution mapping and characterization of open chromatin across the genome.Cell132, 311–322 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  25. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages.Immunity32, 317–328 (2010).

    Article CAS PubMed  Google Scholar 

  26. Heinz, S. et al. Simple combinations of lineage-determining transcription factors primecis-regulatory elements required for macrophage and B cell identities.Mol. Cell38, 576–589 (2010).References 25 and 26 report the first characterization of enhancers in macrophages, identifying PU.1 as a main player.

    Article CAS PubMed PubMed Central  Google Scholar 

  27. Natoli, G. Maintaining cell identity through global control of genomic organization.Immunity33, 12–24 (2010).

    Article CAS PubMed  Google Scholar 

  28. Holtschke, T. et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of theICSBP gene.Cell87, 307–317 (1996).

    Article CAS PubMed  Google Scholar 

  29. Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses.Nature Immunol.12, 231–238 (2011).This important study first described the requirement for IRF5 in the control of M1 macrophage polarization.

    Article CAS  Google Scholar 

  30. Satoh, T. et al. The Jmjd3–Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.Nature Immunol.11, 936–944 (2010).This study demonstrated the role of JMJD3-mediated IRF4 activation in driving M2 macrophage polarization in response to helminths.

    Article CAS  Google Scholar 

  31. Ruffell, D. et al. A CREB–C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair.Proc. Natl Acad. Sci. USA106, 17475–17480 (2009).This elegant study showed that the CREB-dependent induction of C/EBPβ expression is specifically required for M2-like macrophage polarization.

    Article CAS PubMed PubMed Central  Google Scholar 

  32. De Santa, F. et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages.EMBO J.28, 3341–3352 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  33. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling.Cell138, 114–128 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  34. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation.Cell138, 129–145 (2009).References 33 and 34 demonstrated that the presence of a CpG island relieves dependence on chromatin remodelling for inducible gene activation.

    Article CAS PubMed PubMed Central  Google Scholar 

  35. Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription.Genes Dev.25, 1010–1022 (2009).

    Article CAS  Google Scholar 

  36. Ayton, P. M., Chen, E. H. & Cleary, M. L. Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein.Mol. Cell. Biol.24, 10470–10478 (2004).

    Article CAS PubMed PubMed Central  Google Scholar 

  37. Lee, J. H. & Skalnik, D. G. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex.J. Biol. Chem.280, 41725–41731 (2005).

    Article CAS PubMed  Google Scholar 

  38. Lee, J. H. & Skalnik, D. G. Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes.Mol. Cell. Biol.28, 609–618 (2008).

    Article CAS PubMed  Google Scholar 

  39. Valouev, A. et al. Determinants of nucleosome organization in primary human cells.Nature474, 516–520 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  40. Ramirez-Carrozzi, V. R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response.Genes Dev.20, 282–296 (2006).This was the first description of a required role for SWI/SNF-dependent chromatin remodelling in pro-inflammatory gene induction.

    Article CAS PubMed PubMed Central  Google Scholar 

  41. Kayama, H. et al. Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IκBζ.J. Biol. Chem.283, 12468–12477 (2008).

    Article CAS PubMed  Google Scholar 

  42. Nau, G. J. et al. Human macrophage activation programs induced by bacterial pathogens.Proc. Natl Acad. Sci. USA99, 1503–1508 (2002).

    Article CAS PubMed PubMed Central  Google Scholar 

  43. Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic.Nature468, 1119–1123 (2011).This report first demonstrated the possibility of selectively interfering with a subset of pro-inflammatory genes by exploiting chromatin-dependent regulation.

    Article CAS  Google Scholar 

  44. Smale, S. T. Selective transcription in response to an inflammatory stimulus.Cell140, 833–844 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  45. Darnell, J. E., Jr, Kerr, I. M. & Stark, G. R. Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.Science264, 1415–1421 (1994).

    Article CAS PubMed  Google Scholar 

  46. Park, C., Li, S., Cha, E. & Schindler, C. Immune response inStat2 knockout mice.Immunity13, 795–804 (2000).

    Article CAS PubMed  Google Scholar 

  47. Meraz, M. A. et al. Targeted disruption of theStat1 gene in mice reveals unexpected physiologic specificity in the JAK–STAT signaling pathway.Cell84, 431–442 (1996).

    Article CAS PubMed  Google Scholar 

  48. Durbin, J. E., Hackenmiller, R., Simon, M. C. & Levy, D. E. Targeted disruption of the mouseStat1 gene results in compromised innate immunity to viral disease.Cell84, 443–450 (1996).

    Article CAS PubMed  Google Scholar 

  49. Varinou, L. et al. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-γ-dependent innate immunity.Immunity19, 793–802 (2003).

    Article CAS PubMed  Google Scholar 

  50. Kovarik, P., Sauer, I. & Schaljo, B. Molecular mechanisms of the anti-inflammatory functions of interferons.Immunobiology212, 895–901 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  51. Stockinger, S. et al. Characterization of the interferon-producing cell in mice infected withListeria monocytogenes.PLoS Pathog.5, e1000355 (2009).

    Article PubMed CAS PubMed Central  Google Scholar 

  52. Kaplan, D. H. et al. Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice.Proc. Natl Acad. Sci. USA95, 7556–7561 (1998).

    Article CAS PubMed PubMed Central  Google Scholar 

  53. Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective.Annu. Rev. Immunol.27, 451–483 (2009).

    Article CAS PubMed  Google Scholar 

  54. Herbert, D. R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.Immunity20, 623–635 (2004).

    Article CAS PubMed  Google Scholar 

  55. Brombacher, F., Arendse, B., Peterson, R., Holscher, A. & Holscher, C. Analyzing classical and alternative macrophage activation in macrophage/neutrophil-specific IL-4 receptor-α-deficient mice.Methods Mol. Biol.531, 225–252 (2009).

    Article CAS PubMed  Google Scholar 

  56. Takeda, K. et al. Essential role of Stat6 in IL-4 signalling.Nature380, 627–630 (1996).

    Article CAS PubMed  Google Scholar 

  57. Ohmori, Y. & Hamilton, T. A. IL-4-induced STAT6 suppresses IFN-γ-stimulated STAT1-dependent transcription in mouse macrophages.J. Immunol.159, 5474–5482 (1997).

    CAS PubMed  Google Scholar 

  58. Fruman, D. A. et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α.Science283, 393–397 (1999).

    Article CAS PubMed  Google Scholar 

  59. Rauh, M. J. et al. SHIP represses the generation of alternatively activated macrophages.Immunity23, 361–374 (2005).

    Article CAS PubMed  Google Scholar 

  60. DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell16, 91–102 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  61. Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions.Immunity32, 593–604 (2010).

    Article CAS PubMed  Google Scholar 

  62. Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol.72, 219–246 (2010).

    Article CAS PubMed  Google Scholar 

  63. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation.Nature391, 79–82 (1998).This was the first description of the anti-inflammatory function of PPARγ through transrepression of NF-κB and AP1.

    Article CAS PubMed  Google Scholar 

  64. Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ.Nature437, 759–763 (2005).

    Article CAS PubMed PubMed Central  Google Scholar 

  65. Bouhlel, M. A. et al. PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.Cell Metab.6, 137–143 (2007).

    Article CAS PubMed  Google Scholar 

  66. Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance.Nature447, 1116–1120 (2007).References 65 and 66 demonstrated the requirement for PPARγ in M2 macrophage polarization.

    Article CAS PubMed PubMed Central  Google Scholar 

  67. Huang, J. T. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase.Nature400, 378–382 (1999).

    Article CAS PubMed  Google Scholar 

  68. Szanto, A. et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells.Immunity33, 699–712 (2010).This study demonstrated that two key players in M2 macrophage polarization — STAT6 and PPARγ — functionally and physically interact.

    Article CAS PubMed PubMed Central  Google Scholar 

  69. Van Ginderachter, J. A. et al. Peroxisome proliferator-activated receptor γ (PPARγ) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer.Blood108, 525–535 (2006).

    Article CAS PubMed  Google Scholar 

  70. Friedman, A. D. Transcriptional control of granulocyte and monocyte development.Oncogene26, 6816–6828 (2007).

    Article CAS PubMed  Google Scholar 

  71. El Kasmi, K. C. et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.Nature Immunol.9, 1399–1406 (2008).

    Article CAS  Google Scholar 

  72. Hu, H. M., Baer, M., Williams, S. C., Johnson, P. F. & Schwartz, R. C. Redundancy of C/EBPα, -β, and -δ in supporting the lipopolysaccharide-induced transcription of IL-6 and monocyte chemoattractant protein-1.J. Immunol.160, 2334–2342 (1998).

    CAS PubMed  Google Scholar 

  73. Gorgoni, B., Maritano, D., Marthyn, P., Righi, M. & Poli, V. C/EBPβ gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages.J. Immunol.168, 4055–4062 (2002).

    Article CAS PubMed  Google Scholar 

  74. Kim, C. et al. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus.Proc. Natl Acad. Sci. USA105, 6150–6155 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  75. Ananieva, O. et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling.Nature Immunol.9, 1028–1036 (2008).

    Article CAS  Google Scholar 

  76. Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor.Immunity32, 790–802 (2010).An important study demonstrating that MDSC production and activity are crucially linked to C/EBPβ function.

    Article CAS PubMed  Google Scholar 

  77. Youn, J. I. & Gabrilovich, D. I. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity.Eur. J. Immunol.40, 2969–2975 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  78. Gallina, G. et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.J. Clin. Invest.116, 2777–2790 (2006).The first description of MDSCs in the context of tumour-induced immune suppression.

    Article CAS PubMed PubMed Central  Google Scholar 

  79. Savitsky, D., Tamura, T., Yanai, H. & Taniguchi, T. Regulation of immunity and oncogenesis by the IRF transcription factor family.Cancer Immunol. Immunother.59, 489–510 (2010).

    Article CAS PubMed  Google Scholar 

  80. De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.Cell130, 1083–1094 (2007).This study reports the cloning ofJmjd3 and provides an initial description of its role in macrophage function.

    Article CAS PubMed  Google Scholar 

  81. Ishii, M. et al. Epigenetic regulation of the alternatively activated macrophage phenotype.Blood114, 3244–3254 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  82. El Chartouni, C., Schwarzfischer, L. & Rehli, M. Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming.Immunobiology215, 821–825 (2010).

    Article CAS PubMed  Google Scholar 

  83. Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.Nature434, 243–249 (2005).

    Article CAS PubMed  Google Scholar 

  84. 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).

    Article CAS PubMed  Google Scholar 

  85. Gilchrist, M. et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.Nature441, 173–178 (2006).

    Article CAS PubMed  Google Scholar 

  86. Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties.Immunity19, 71–82 (2003).This was the first characterization of two distinct populations of blood monocytes with different recruitment and functional properties.

    Article CAS PubMed  Google Scholar 

  87. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.J. Exp. Med.204, 3037–3047 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  88. Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.J. Exp. Med.204, 1057–1069 (2007).An excellent illustration of the dynamic nature of mononuclear phagocyte phenotype during inflammation.

    Article CAS PubMed PubMed Central  Google Scholar 

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Acknowledgements

T.L. is a research director of the Institut National de la Santé et de la Recherche Médicale (INSERM) supported by grants from the European Research Council (ERC) and the Agence Nationale de la Recherche (ANR), and institutional grants from INSERM, the Centre National de la Recherche Scientifique (CNRS) and the Université de la Méditerranée. Research in this area in the laboratory of G.N. is supported by the ERC.

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Authors and Affiliations

  1. Centre d'Immunologie Marseille-Luminy, Parc Scientifique & Technologique de Luminy, Case 906, Marseille, F-13288, France

    Toby Lawrence

  2. Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, Milan, 20139, Italy

    Gioacchino Natoli

Authors
  1. Toby Lawrence
  2. Gioacchino Natoli

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Correspondence toToby Lawrence orGioacchino Natoli.

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Glossary

Mononuclear phagocyte system

(MPS). A group of bone marrow-derived cells with different morphologies (monocytes, macrophages and dendritic cells), which are mainly responsible for phagocytosis, cytokine secretion and antigen presentation.

M1 macrophages

Macrophages with an activation phenotype associated with increased microbicidal activity and antigen-presenting function. M1-type activation is usually modelledin vitro by interferon-γ and/or lipopolysaccharide stimulation. In mice, M1-associated markers include interleukin-12, MHC class II molecules and nitric oxide synthase 2 (NOS2); however, human macrophages do not show induction of NOS2 in these conditions, despite having a similar functional phenotype.

M2 macrophages

Macrophages that are associated with parasitic infections and T helper 2-type immune responses. M2-type activation is usually modelledin vitro by interleukin-4 (IL-4) and/or IL-13 stimulation. In mice, M2-associated markers include resistin-like-α (also known as FIZZ1), arginase 1, chitinase 3-like 3 (also known as YM1), IL-10 and macrophage mannose receptor 1 (also known as CD206); however, human M2 macrophages do not show induction of resistin-like-α, arginase 1 and chitinase 3-like 3, but instead upregulate indoleamine 2,3-dioxygenase expression. M2 macrophages are associated with anti-inflammatory and homeostatic functions linked to wound healing, fibrosis and tissue repair.

Chromatin immunoprecipitation

(ChIP). A powerful method for assessing the physical association of a known nuclear protein with a candidate target locusin vivo. Cells are first treated with an agent that crosslinks protein to DNA. The chromatin is then sheared into fragments and the protein is immunoprecipitated. If the candidate target region is co-precipitated (as measured by PCR), the target locus is likely to bind the protein (directly or indirectly)in vivo. The immunoprecipitated DNA can also be used for hybridization to high-density microarrays (ChIP–chip) or for high-throughput sequencing (ChIP–seq) to provide a genome-wide view of the binding sites of a specific transcriptional regulator.

Gene promoters

The regulatory regions to which RNA polymerase binds to initiate transcription. Upstream of the RNA polymerase recruitment site (core promoter) is a regulatory promoter where transcription factors bind to control recruitment of the transcriptional machinery.

Enhancers

Control elements located at variable distances from the genes they regulate and to which multiple regulatory proteins bind, thereby influencing gene transcription.In vitro, enhancers function in an orientation- and position-independent manner, but it is not clear whether this is also truein vivo.

Primary response genes

Inducible genes whose transcription does not require new protein synthesis.

Secondary response genes

Inducible genes whose transcription requires new protein synthesis (often the synthesis of transcription factors required for the activation of these genes).

SWI/SNF complex

An ATP-dependent chromatin-remodelling protein complex that was initially identified in yeast. Related complexes exist in mammals and are involved in the remodelling of the chromatin of various genes.

Gamma-activated sequences

DNA binding sites specific for signal transducer and activator of transcription 1 (STAT1) homodimers that mediate the response to interferon-γ.

Interferon-stimulated response elements

(ISREs). Common DNA motifs that are bound by interferon-regulatory factors (IRFs). These elements were initially known as IRF enhancers (IRFEs).

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Lawrence, T., Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity.Nat Rev Immunol11, 750–761 (2011). https://doi.org/10.1038/nri3088

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