Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transcriptional and epigenetic regulation of macrophages in atherosclerosis

Abstract

Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.

Key points

  • Atherosclerotic plaques contain a complex environment with different activation signals that result in intraplaque macrophage heterogeneity.

  • Plasticity of macrophage phenotype is modulated by an interplay between transcription factors and epigenetic enzymes.

  • Signalling pathways in inflammation have an extensive molecular crosstalk.

  • Modulating transcription factor activity is a promising therapeutic target for atherosclerosis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Epigenetic landscape of DNA regulatory regions.
Fig. 2: Macrophage enhancer selection.
Fig. 3: Transcription factors modulate macrophage phenotypes in atherosclerosis.

References

  1. 1.

    Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nat. Rev. Cardiol. 7, 77–86 (2010).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Gordon, S. & Plüddemann, A. Tissue macrophages: heterogeneity and functions. BMC Biol. 15, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Ginhoux, F., Schultze, J. L., Murray, P. J., Ochando, J. & Biswas, S. K. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat. Immunol. 17, 34–40 (2016).

    CAS  PubMed  Google Scholar 

  4. 4.

    Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Colin, S., Chinetti-Gbaguidi, G. & Staels, B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 262, 153–166 (2014).

    CAS  PubMed  Google Scholar 

  6. 6.

    Schultze, J. L., Schmieder, A. & Goerdt, S. Macrophage activation in human diseases. Semin. Immunol. 27, 249–256 (2015).

    CAS  PubMed  Google Scholar 

  7. 7.

    Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).

    CAS  PubMed  Google Scholar 

  9. 9.

    Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).

    CAS  PubMed  Google Scholar 

  10. 10.

    Talbert, P. B. & Henikoff, S. Histone variants — ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol. 11, 264–275 (2010).

    CAS  PubMed  Google Scholar 

  11. 11.

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  12. 12.

    Hoeksema, M. A. & de Winther, M. P. J. Epigenetic regulation of monocyte and macrophage function. Antioxid. Redox Signal. 25, 758–774 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Schmidt, S. V. et al. The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin. Cell Res. 26, 151–170 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    CAS  PubMed  Google Scholar 

  19. 19.

    Javierre, B. M. et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell 167, 1369–1384.e19 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Phanstiel, D. H. et al. Static and dynamic DNA loops form AP-1-bound activation hubs during macrophage development. Mol. Cell 67, 1037–1048.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Schübeler, D. Function and information content of DNA methylation. Nature 517, 321–326 (2015).

    PubMed  Google Scholar 

  23. 23.

    Bock, C. et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell 47, 633–647 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Vento-Tormo, R. et al. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol. 17, 4 (2016).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Dekkers, K. F., Neele, A. E., Jukema, J. W., Heijmans, B. T. & de Winther, M. P. J. Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites. Epigenetics Chromatin 12, 34 (2019).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Katayama, S. et al. Antisense transcription in the mammalian transcriptome. Science 309, 1564–1566 (2005).

    Google Scholar 

  28. 28.

    Li, H., Jiang, T., Li, M.-Q., Zheng, X.-L. & Zhao, G.-J. Transcriptional regulation of macrophages polarization by microRNAs. Front. Immunol. 9, 3–12 (2018).

    Google Scholar 

  29. 29.

    Zhang, Z., Salisbury, D. & Sallam, T. Long noncoding RNAs in atherosclerosis: JACC review topic of the week. J. Am. Coll. Cardiol. 72, 2380–2390 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

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

    CAS  PubMed  Google Scholar 

  31. 31.

    Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    CAS  PubMed  Google Scholar 

  32. 32.

    Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).

    CAS  Google Scholar 

  33. 33.

    Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Cheng, S. C. et al. mTOR- and HIF-1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Bekkering, S. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol. 34, 1731–1738 (2014).

    CAS  PubMed  Google Scholar 

  37. 37.

    Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89–100.e5 (2018).

    CAS  PubMed  Google Scholar 

  38. 38.

    Ifrim, D. C. et al. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin. Vaccine Immunol. 21, 534–545 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Yoshida, K. et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat. Immunol. 16, 1034–1043 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–155.e12 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–168.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Seijkens, T. et al. Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis. FASEB J. 28, 2202–2213 (2014).

    CAS  PubMed  Google Scholar 

  43. 43.

    Vierbuchen, T. et al. AP-1 transcription factors and the BAF complex mediate signal-dependent enhancer selection. Mol. Cell. 68, 1067–1082.e12 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Herrington, W., Lacey, B., Sherliker, P., Armitage, J. & Lewington, S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ. Res. 118, 535–546 (2016).

    CAS  PubMed  Google Scholar 

  45. 45.

    GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1151–1210 (2017).

    Google Scholar 

  46. 46.

    Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018).

    Google Scholar 

  47. 47.

    Stöger, J. L. et al. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis 225, 461–468 (2012).

    PubMed  Google Scholar 

  48. 48.

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

    CAS  PubMed  Google Scholar 

  49. 49.

    Benoit, M., Desnues, B. & Mege, J. L. Macrophage polarization in bacterial infections. J. Immunol. 181, 3733–3739 (2008).

    CAS  PubMed  Google Scholar 

  50. 50.

    Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, (593–604 (2010).

    Google Scholar 

  51. 51.

    Müller, U. et al. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J. Immunol. 179, 5367–5377 (2007).

    PubMed  Google Scholar 

  52. 52.

    Spiller, K. L. et al. Differential gene expression in human, murine, and cell line-derived macrophages upon polarization. Exp. Cell Res. 347, 1–13 (2016).

    CAS  PubMed  Google Scholar 

  53. 53.

    Tugal, D., Liao, X. & Jain, M. K. Transcriptional control of macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 33, 1135–1144 (2013).

    CAS  PubMed  Google Scholar 

  54. 54.

    Oh, K.-S. et al. Dual roles for ikaros in regulation of macrophage chromatin state and inflammatory gene expression. J. Immunol. 201, 757–771 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Liu, T., Zhang, L., Joo, D. & Sun, S.-C. NF-κB signaling in inflammation. Signal Transduct. Target Ther. 2, 17023 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Dorrington, M. G. & Fraser, I. D. C. NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Front. Immunol. 10, 705 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

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

    CAS  PubMed  Google Scholar 

  58. 58.

    Günthner, R. & Anders, H.-J. Interferon-regulatory factors determine macrophage phenotype polarization. Mediators Inflamm. 2013, 731023 (2013).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Mancino, A. et al. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev. 29, 394–408 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Saliba, D. G. et al. IRF5:RelA interaction targets inflammatory genes in macrophages. Cell Rep. 8, 1308–1317 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Szanto, A. et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells. Immunity 33, 699–712 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Czimmerer, Z. et al. The transcription factor stat6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity 48, 75–76 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chistiakov, D. A., Melnichenko, A. A., Myasoedova, V. A., Grechko, A. V. & Orekhov, A. N. Mechanisms of foam cell formation in atherosclerosis. J. Mol. Med. 95, 1153–1165 (2017).

    CAS  PubMed  Google Scholar 

  64. 64.

    Tangirala, R. K. et al. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl Acad. Sci. USA 99, 11896–11901 (2002).

    CAS  PubMed  Google Scholar 

  65. 65.

    Kim, K. et al. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ. Res. 123, 1127–1142 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Wolfs, I. M., Donners, M. M. & de Winther, M. P. Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb. Haemost. 106, 763–771 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Tall, A. R. & Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 15, 104–116 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122, 707–721 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Ghisletti, S. et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol. Cell 25, 57–70 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Ghisletti, S. et al. Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. Genes Dev. 23, 681–693 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Daniel, B. et al. The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages. Nucleic Acids Res. 46, 4425–4439 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Daniel, B. et al. The nuclear receptor PPARγ; controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory. Immunity 49, 615–616 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gold, E. S. et al. ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation. J. Exp. Med. 209, 807–817 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    De Nardo, D. et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat. Immunol. 15, 152–160 (2014).

    PubMed  Google Scholar 

  75. 75.

    Li, Z. et al. Krüppel-like factor 4 regulation of cholesterol-25-hydroxylase and liver x receptor mitigates atherosclerosis susceptibility. Circulation 136, 1315–1330 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Hamada, M. et al. MafB promotes atherosclerosis by inhibiting foam-cell apoptosis. nature communications. Nat. Commun. 5, 3147 (2014).

    PubMed  Google Scholar 

  77. 77.

    Hasegawa, H. et al. The role of macrophage transcription factor MafB in atherosclerotic plaque stability. Atherosclerosis 250, 133–143 (2016).

    CAS  PubMed  Google Scholar 

  78. 78.

    Dubland, J. A. & Francis, G. A. So much cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation. Curr. Opin. Lipidol. 27, 155–161 (2016).

    CAS  PubMed  Google Scholar 

  79. 79.

    Holycross, B. J., Blank, R. S., Thompson, M. M., Peach, M. J. & Owens, G. K. Platelet-derived growth factor-BB-induced suppression of smooth muscle cell differentiation. Circ. Res. 71, 1525–1532 (1992).

    CAS  PubMed  Google Scholar 

  80. 80.

    Barrett, T. B. & Benditt, E. P. Platelet-derived growth factor gene expression in human atherosclerotic plaques and normal artery wall. Proc. Natl Acad. Sci. USA 85, 2810–2814 (1988).

    CAS  PubMed  Google Scholar 

  81. 81.

    Owens, G. K., Kumar, M. S. & Wamhoff, B. R. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 84, 767–801 (2004).

    CAS  PubMed  Google Scholar 

  82. 82.

    Williams, K. J. & Tabas, I. The response-to-retention hypothesis of early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 15, 551–561 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Ma, S., Yang, D., Li, D., Tang, B. & Yang, Y. Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36. Lipids Health Dis. 10, 53 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Costales, P. et al. K domain CR9 of low density lipoprotein (LDL) receptor-related protein 1 (LRP1) is critical for aggregated LDL-induced foam cell formation from human vascular smooth muscle cells. J. Biol. Chem. 290, 14852–14865 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Rivera, J. et al. Accumulation of serum lipids by vascular smooth muscle cells involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter A1. Naunyn Schmiedebergs Arch. Pharmacol. 386, 1081–1093 (2013).

    CAS  PubMed  Google Scholar 

  86. 86.

    Rong, J. X., Shapiro, M., Trogan, E. & Fisher, E. A. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc. Natl Acad. Sci. USA 100, 13531–13536 (2003).

    CAS  PubMed  Google Scholar 

  87. 87.

    Allahverdian, S., Chehroudi, A. C., McManus, B. M., Abraham, T. & Francis, G. A. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129, 1551–1559 (2014).

    CAS  PubMed  Google Scholar 

  88. 88.

    Shankman, L. S. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 21, 628–637 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Deaton, R. A., Gan, Q. & Owens, G. K. Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. Am. J. Physiol. Heart Circ. Physiol. 296, H1027–H1037 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kapoor, N. et al. Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. J. Immunol. 194, 6011–6023 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Vengrenyuk, Y. et al. Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 535–546 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Feil, S. et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ. Res. 115, 662–667 (2014).

    CAS  PubMed  Google Scholar 

  93. 93.

    Huff, M. W. & Pickering, J. G. Can a vascular smooth muscle-derived foam-cell really change its spots? Arterioscler. Thromb. Vasc. Biol. 35, 492–495 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Li, B. et al. Kallistatin inhibits atherosclerotic inflammation by regulating macrophage polarization. Hum. Gene Ther. 30, 339–351 (2019).

    CAS  PubMed  Google Scholar 

  95. 95.

    Chen, W. et al. Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis. Int. Immunopharmacol. 70, 486–497 (2019).

    CAS  PubMed  Google Scholar 

  96. 96.

    Tang, R.-Z. et al. DNA methyltransferase 1 and Krüppel-like factor 4 axis regulates macrophage inflammation and atherosclerosis. J. Mol. Cell Cardiol. 128, 11–24 (2019).

    CAS  PubMed  Google Scholar 

  97. 97.

    Ivashkiv, L. B. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 34, 216–223 (2013).

    CAS  PubMed  Google Scholar 

  98. 98.

    Mullican, S. E. et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 25, 2480–2488 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Hoeksema, M. A. et al. Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol. Med. 6, 1124–1132 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    You, S.-H. et al. Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo. Nat. Struct. Mol. Biol. 20, 182–187 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Li, P. et al. NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell 155, 200–214 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Cao, Q. et al. Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscler. Thromb. Vasc. Biol. 34, 1871–1879 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    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  PubMed  Google Scholar 

  104. 104.

    Neele, A. E. et al. Macrophage Kdm6b controls the pro-fibrotic transcriptome signature of foam cells. Epigenomics 9, 383–391 (2017).

    CAS  PubMed  Google Scholar 

  105. 105.

    Neele, A. E. et al. Myeloid Kdm6b deficiency results in advanced atherosclerosis. Atherosclerosis 275, 156–165 (2018).

    CAS  PubMed  Google Scholar 

  106. 106.

    Hsu, A. T. et al. Epigenetic and transcriptional regulation of IL4-induced CCL17 production in human monocytes and murine macrophages. J. Biol. Chem. 293, 11415–11423 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Achuthan, A. et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J. Clin. Invest. 126, 3453–3466 (2016).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Lehtonen, A., Matikainen, S., Miettinen, M. & Julkunen, I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J. Leukoc. Biol. 71, 511–519 (2002).

    CAS  PubMed  Google Scholar 

  109. 109.

    Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231–238 (2011).

    CAS  PubMed  Google Scholar 

  110. 110.

    Zhang, X. et al. Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. J. Exp. Med. 215, 1365–1382 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Sun, J. et al. SIRT1 activation disrupts maintenance of myelodysplastic syndrome stem and progenitor cells by restoring TET2 function. Cell Stem Cell 23, 355–359 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Stein, S. & Matter, C. M. Protective roles of SIRT1 in atherosclerosis. Cell Cycle 10, 640–647 (2014).

    Google Scholar 

  115. 115.

    Sano., S. et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ. Res. 123, 335–341 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Li, X. et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17, 806–815 (2016).

    CAS  PubMed  Google Scholar 

  117. 117.

    Lin, J.-D. et al. Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight 4, e124574 (2019).

    PubMed Central  Google Scholar 

  118. 118.

    Piccolo, V. et al. Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk. Nat. Immunol. 18, 530–540 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Qiao, Y., Kang, K., Giannopoulou, E., Fang, C. & Ivashkiv, L. B. IFN-γ induces histone 3 lysine 27 trimethylation in a small subset of promoters to stably silence gene expression in human macrophages. Cell Rep. 16, 3121–3129 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Kang, K. et al. Interferon-γ represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF. Immunity 47, 235–250.e4 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Eichenfield, D. Z. et al. Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages. eLife 5, e13024 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Park, S. H. et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 18, 1104–1116 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Neele, A. E., Van den Bossche, J., Hoeksema, M. A. & de Winther, M. P. J. Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis. Eur. J. Pharmacol. 763, 79–89 (2015).

    CAS  PubMed  Google Scholar 

  124. 124.

    Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Parnas, O. et al. A genome-wide CRISPR screen in primary immune cells to dissect regulatory networks. Cell 162, 675–686 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Dixit, A. et al. Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1857.e17 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of M.P.J.de W. and C.K.G. is supported by The Netherlands Heart Foundation (GENIUS (CVON 2011/B019) and GENIUS2 (CVON 2017–20) to M.P.J.de W.); The Netherlands Heart Foundation and Spark-Holding BV (2015B002 to M.P.J.de W.); the European Union (ITN grant EPIMAC to M.P.J.de W.); NIH grants (DK063491, DK091183 and HL088093 to C.K.G.); and Foundation Leducq (LEAN Transatlantic Network Grant to M.P.J.de W. and C.K.G.).

Author information

Affiliations

Authors

Contributions

All the authors researched data for the article, discussed its content, wrote the manuscript and reviewed and edited it before submission.

Corresponding author

Correspondence to Menno P. J. de Winther.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Transcription factors

Proteins with a DNA-binding domain that guide the transcriptional machinery to or block it from regulatory elements such as promoters and enhancers, thereby facilitating the execution of tailored transcriptional programmes.

Long-range interactions

Interactions between regulatory DNA regions that occur over large linear distances, predominantly between enhancers and between enhancers and promoters. These interactions can have a regulatory role.

Promoters

Regulatory DNA regions proximal to a transcription start site. Contain consensus motifs for transcription factors and the transcriptional machinery.

Enhancers

Regulatory DNA regions distal to a transcription start site. Contain transcription factor binding sites that can regulate the transcription of target genes independently of linear distance.

Histone-modifying enzymes

(HMEs). Readers, writers or erasers of chemical histone (tail) modifications.

Lineage-determining transcription factors

(LDTFs). Transcription factors with pioneering (that is, chromatin conformation-changing) capabilities that set up the chromatin for execution of cell type-specific gene programmes.

Signal-dependent transcription factors

(SDTFs). Transcription factors that bind DNA and activate its gene programme in response to an external stimulus.

CpG islands

Genomic regions with a higher-than-average frequency of CpG sites, typically defined as a region of 500–1,500 bp in length, with CpG content >50% and an observed/expected CpG ratio of >0.6; CpG islands often occur in gene regulatory regions, and their DNA methylation status regulates genomic structures and gene transcription.

Histone marks

Chemical groups covalently bound to a specific amino acid residue on (the tail of) a histone protein. Histone marks can change the local chromatin accessibility through electrostatic effects and/or guide the transcription machinery to specific loci in the genome (Box 1).

Euchromatin

A permissive chromatin state in which the chromatin is in an open conformation accessible to the transcription machinery.

Heterochromatin

A repressive chromatin state in which the chromatin is in a closed conformation inaccessible to transcription factors.

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). Method for genome-wide identification of open chromatin regions with potential regulatory function.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kuznetsova, T., Prange, K.H.M., Glass, C.K. et al. Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nat Rev Cardiol 17, 216–228 (2020). https://doi.org/10.1038/s41569-019-0265-3

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing