Review Article | Published:

Myeloid cell contributions to cardiovascular health and disease

Nature Medicinevolume 24pages711720 (2018) | Download Citation

Abstract

Recent advances in cell tracing and sequencing technologies have expanded our knowledge on leukocyte behavior. As a consequence, inflammatory cells, such as monocyte-derived macrophages, and their actions and products are increasingly being considered as potential drug targets for treatment of atherosclerosis, myocardial infarction and heart failure. Particularly promising developments are the identification of harmful arterial and cardiac macrophage subsets, the cells’ altered, sometimes even clonal production in hematopoietic organs, and epigenetically entrained memories of myeloid progenitors and macrophages in the setting of cardiovascular disease. Given the roles of monocytes and macrophages in host defense, intricately understanding the involved cellular subsets, sources and functions is essential for the design of precision therapeutics that preserve protective innate immunity. Here I review how new clinical and preclinical data, often linking the cardiovascular, immune and other organ systems, propel conceptual advances to a point where cardiovascular immunotherapy appears within reach.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

  2. 2.

    Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

  3. 3.

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

  4. 4.

    Courties, G. et al. Ischemic stroke activates hematopoietic bone marrow stem cells. Circ. Res. 116, 407–417 (2015).

  5. 5.

    Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

  6. 6.

    Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014).

  7. 7.

    Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).

  8. 8.

    Murphy, A. J. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J. Clin. Invest. 121, 4138–4149 (2011).

  9. 9.

    Robbins, C. S. et al. Extramedullary hematopoiesis generates Ly-6Chigh monocytes that infiltrate atherosclerotic lesions. Circulation 125, 364–374 (2012).

  10. 10.

    Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

  11. 11.

    Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).

  12. 12.

    Ensan, S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159–168 (2016).

  13. 13.

    Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

  14. 14.

    Hulsmans, M. et al. Macrophages facilitate electrical conduction in the heart. Cell 169, 510–522.e20 (2017).

  15. 15.

    King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017).

  16. 16.

    Lavine, K. J. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. USA 111, 16029–16034 (2014).

  17. 17.

    Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. https://doi.org/10.1161/CIRCRESAHA.117.312509 (2018).

  18. 18.

    Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. https://doi.org/10.1161/CIRCRESAHA.117.312513 (2018).

  19. 19.

    Epelman, S., Liu, P. P. & Mann, D. L. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat. Rev. Immunol. 15, 117–129 (2015).

  20. 20.

    Heidt, T. et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ. Res. 115, 284–295 (2014).

  21. 21.

    Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).

  22. 22.

    Nabel, E. G. & Braunwald, E. A tale of coronary artery disease and myocardial infarction. N. Engl. J. Med. 366, 54–63 (2012).

  23. 23.

    Ridker, P. M. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur. Heart J. 37, 1720–1722 (2016).

  24. 24.

    Libby, P., Lichtman, A. H. & Hansson, G. K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38, 1092–1104 (2013).

  25. 25.

    Roufaiel, M. et al. CCL19–CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima. Nat. Immunol. 17, 1263–1272 (2016).

  26. 26.

    Pinto, A. R. et al. Age-related changes in tissue macrophages precede cardiac functional impairment. Aging (Albany NY) 6, 399–413 (2014).

  27. 27.

    Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

  28. 28.

    Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. in the press (2018).

  29. 29.

    Leid, J. et al. Primitive embryonic macrophages are required for coronary development and maturation. Circ. Res. 118, 1498–1511 (2016).

  30. 30.

    Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).

  31. 31.

    Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).

  32. 32.

    Hulsmans, M. et al. Cardiac macrophages promote diastolic dysfunction. J. Exp. Med. 215, 423–440 (2018).

  33. 33.

    Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).

  34. 34.

    Frustaci, A. et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96, 1180–1184 (1997).

  35. 35.

    Yamashita, T. et al. Recruitment of immune cells across atrial endocardium in human atrial fibrillation. Circ. J. 74, 262–270 (2010).

  36. 36.

    Aviles, R. J. et al. Inflammation as a risk factor for atrial fibrillation. Circulation 108, 3006–3010 (2003).

  37. 37.

    Dernellis, J. & Panaretou, M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur. Heart J. 25, 1100–1107 (2004).

  38. 38.

    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).

  39. 39.

    McArdle, S., Chodaczek, G., Ray, N. & Ley, K. Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries. J. Biomed. Opt. 20, 26005 (2015).

  40. 40.

    McArdle, S., Mikulski, Z. & Ley, K. Live cell imaging to understand monocyte, macrophage, and dendritic cell function in atherosclerosis. J. Exp. Med. 213, 1117–1131 (2016).

  41. 41.

    Wang, Y. et al. Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171, 331–345.e22 (2017).

  42. 42.

    Nowotschin, S. & Hadjantonakis, A. K. Use of KikGR a photoconvertible green-to-red fluorescent protein for cell labeling and lineage analysis in ES cells and mouse embryos. BMC Dev. Biol. 9, 49 (2009).

  43. 43.

    Quintar, A. et al. Endothelial protective monocyte patrolling in large arteries intensified by western diet and atherosclerosis. Circ. Res. 120, 1789–1799 (2017).

  44. 44.

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

  45. 45.

    Yan, X. et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J. Mol. Cell. Cardiol. 62, 24–35 (2013).

  46. 46.

    Hilgendorf, I. et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ. Res. 114, 1611–1622 (2014).

  47. 47.

    van der Laan, A. M. et al. Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir. Eur. Heart J. 35, 376–385 (2014).

  48. 48.

    Li, W. et al. Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling. JCI Insight 1, e87315 (2016).

  49. 49.

    Carlin, L. M. et al. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).

  50. 50.

    Walter, W. et al. Deciphering the dynamic transcriptional and post-transcriptional networks of macrophages in the healthy heart and after myocardial injury. Cell Reports 23, 622–636 (2018).

  51. 51.

    Sager, H. B. et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ. Res. 119, 853–864 (2016).

  52. 52.

    Thomas, G. D. et al. Human blood monocyte subsets: a new gating strategy defined using cell surface markers identified by mass cytometry. Arterioscler. Thromb. Vasc. Biol. 37, 1548–1558 (2017).

  53. 53.

    Lee, W. W. et al. PET/MRI of inflammation in myocardial infarction. J. Am. Coll. Cardiol. 59, 153–163 (2012).

  54. 54.

    Frangogiannis, N. G. et al. Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation 98, 699–710 (1998).

  55. 55.

    Hofmann, U. et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 125, 1652–1663 (2012).

  56. 56.

    Saxena, A. et al. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am. J. Physiol. Heart Circ. Physiol. 307, H1233–H1242 (2014).

  57. 57.

    Zouggari, Y. et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat. Med. 19, 1273–1280 (2013).

  58. 58.

    Sager, H. B. et al. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci. Transl. Med. 8, 342ra80 (2016).

  59. 59.

    Anzai, A. et al. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J. Exp. Med. 214, 3293–3310 (2017).

  60. 60.

    Madjid, M., Awan, I., Willerson, J. T. & Casscells, S. W. Leukocyte count and coronary heart disease: implications for risk assessment. J. Am. Coll. Cardiol. 44, 1945–1956 (2004).

  61. 61.

    Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).

  62. 62.

    Patel, A. A. et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J. Exp. Med. 214, 1913–1923 (2017).

  63. 63.

    Dutta, P. et al. Myocardial infarction activates CCR2+ hematopoietic stem and progenitor cells. Cell Stem Cell 16, 477–487 (2015).

  64. 64.

    Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

  65. 65.

    Sager, H. B. et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation 132, 1880–1890 (2015).

  66. 66.

    Emami, H. et al. Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc. Imaging 8, 121–130 (2015).

  67. 67.

    Tawakol, A. et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389, 834–845 (2017).

  68. 68.

    Schmidt, M. I. et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 353, 1649–1652 (1999).

  69. 69.

    Ferraro, F. et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci. Transl. Med. 3, 104ra101 (2011).

  70. 70.

    Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).

  71. 71.

    Oikawa, A. et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler. Thromb. Vasc. Biol. 30, 498–508 (2010).

  72. 72.

    Nagareddy, P. R. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821–835 (2014).

  73. 73.

    Rosengren, A. et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 364, 953–962 (2004).

  74. 74.

    Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

  75. 75.

    Jan, M., Ebert, B. L. & Jaiswal, S. Clonal hematopoiesis. Semin. Hematol. 54, 43–50 (2017).

  76. 76.

    Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

  77. 77.

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

  78. 78.

    Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).

  79. 79.

    Álvarez-Errico, D., Vento-Tormo, R., Sieweke, M. & Ballestar, E. Epigenetic control of myeloid cell differentiation, identity and function. Nat. Rev. Immunol. 15, 7–17 (2015).

  80. 80.

    Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).

  81. 81.

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

  82. 82.

    Bekkering, S. et al. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis 254, 228–236 (2016).

  83. 83.

    Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175.e14 (2018).

  84. 84.

    Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).

  85. 85.

    Ridker, P. M. et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391, 319–328 (2018).

  86. 86.

    Brindle, K. New approaches for imaging tumour responses to treatment. Nat. Rev. Cancer 8, 94–107 (2008).

  87. 87.

    Wan, E. et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid–epithelial–reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ. Res. 113, 1004–1012 (2013).

  88. 88.

    Howangyin, K. Y. et al. Myeloid–epithelial–reproductive receptor tyrosine kinase and milk fat globule epidermal growth factor 8 coordinately improve remodeling after myocardial infarction via local delivery of vascular endothelial growth factor. Circulation 133, 826–839 (2016).

  89. 89.

    A-Gonzalez, N. et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J. Exp. Med. 214, 1281–1296 (2017).

  90. 90.

    DeBerge, M. et al. MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury. Circ. Res. 121, 930–940 (2017).

  91. 91.

    Ziegler, K. A. et al. Local sympathetic denervation attenuates myocardial inflammation and improves cardiac function after myocardial infarction in mice. Cardiovasc. Res. 1, 291–299 (2018).

  92. 92.

    Kain, V. et al. Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. J. Mol. Cell. Cardiol. 84, 24–35 (2015).

  93. 93.

    Kaikita, K. et al. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am. J. Pathol. 165, 439–447 (2004).

  94. 94.

    Dewald, O. et al. CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ. Res. 96, 881–889 (2005).

  95. 95.

    Majmudar, M. D. et al. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 127, 2038–2046 (2013).

  96. 96.

    Shiraishi, M. et al. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J. Clin. Invest. 126, 2151–2166 (2016).

  97. 97.

    Tsujioka, H. et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J. Am. Coll. Cardiol. 54, 130–138 (2009).

  98. 98.

    Haubner, B. J. et al. Functional recovery of a human neonatal heart after severe myocardial infarction. Circ. Res. 118, 216–221 (2016).

  99. 99.

    Godwin, J. W., Pinto, A. R. & Rosenthal, N. A. Macrophages are required for adult salamander limb regeneration. Proc. Natl Acad. Sci. USA 110, 9415–9420 (2013).

  100. 100.

    Chow, A. et al. Bone marrow CD169+. macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

  101. 101.

    Ben-Mordechai, T. et al. Macrophage subpopulations are essential for infarct repair with and without stem cell therapy. J. Am. Coll. Cardiol. 62, 1890–1901 (2013).

  102. 102.

    Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).

  103. 103.

    Tothova, Z. et al. Multiplex CRISPR/Cas9-based genome editing in human hematopoietic stem cells models clonal hematopoiesis and myeloid neoplasia. Cell Stem Cell 21, 547–555.e8 (2017).

  104. 104.

    Dever, D. P. et al. CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389 (2016).

  105. 105.

    Yin, H. et al. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. Nat. Biotechnol. 35, 1179–1187 (2017).

  106. 106.

    Luo, Y. L. et al. Macrophage-specific in vivo gene editing using cationic lipid-assisted polymeric nanoparticles. ACS Nano 12, 994–1005 (2018).

  107. 107.

    Vandoorne, K. & Nahrendorf, M. Multiparametric imaging of organ system interfaces. Circ Cardiovasc Imaging 10, e005613 (2017).

  108. 108.

    Acar, M. et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126–130 (2015).

  109. 109.

    Lee, S. et al. Real-time in vivo imaging of the beating mouse heart at microscopic resolution. Nat. Commun. 3, 1054 (2012).

  110. 110.

    Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).

  111. 111.

    Abkowitz, J. L., Catlin, S. N., McCallie, M. T. & Guttorp, P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100, 2665–2667 (2002).

  112. 112.

    Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

  113. 113.

    Mendelson, A. & Frenette, P. S. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat. Med. 20, 833–846 (2014).

Download references

Acknowledgements

This work was funded in part by federal funds from the National Institutes of Health NS084863, HL139598, HL128264, HL117829, HL096576 and HL131495; the European Union’s Horizon 2020 research and innovation program under grant agreement no. 667837; the Global Research Lab (GRL) program (NRF-2015K1A1A2028228) of the National Research Foundation by the Korean government and the MGH Research Scholar Program.

Author information

Affiliations

  1. Center for Systems Biology and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Matthias Nahrendorf

Authors

  1. Search for Matthias Nahrendorf in:

Competing interests

The author declares no competing interests.

Corresponding author

Correspondence to Matthias Nahrendorf.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41591-018-0064-0