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Cardioimmunology: the immune system in cardiac homeostasis and disease

Abstract

The past few decades have generated growing recognition that the immune system makes an important contribution to cardiac development, composition and function. Immune cells infiltrate the heart at gestation and remain in the myocardium, where they participate in essential housekeeping functions throughout life. After myocardial infarction or in response to infection, large numbers of immune cells are recruited to the heart to remove dying tissue, scavenge pathogens and promote healing. Under some circumstances, immune cells can cause irreversible damage, contributing to heart failure. This Review focuses on the role of the immune system in the heart under both homeostatic and perturbed conditions.

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Fig. 1: Cardiac anatomy with respect to immune cells.
Fig. 2: Participation of macrophages in normal electrical conduction.
Fig. 3: Immune cells in coronary heart disease.
Fig. 4: Potential immune mechanisms in viral myocarditis.

References

  1. 1.

    Ramos, G. C. et al. Myocardial aging as a T cell-mediated phenomenon. Proc. Natl Acad. Sci. USA 114, E2420–E2429 (2017).This manuscript provides a cardiac immune cell atlas during ageing.

    CAS  PubMed  Google Scholar 

  2. 2.

    Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    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 

  4. 4.

    Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  5. 5.

    Hoeffel, G. et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    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 

  7. 7.

    Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  8. 8.

    van Furth, R. & Cohn, Z. A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nag, A. C. Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios 28, 41–61 (1980).

    CAS  PubMed  Google Scholar 

  10. 10.

    Pinto, A. R. et al. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLOS ONE 7, e36814 (2012).This study uses a macrophage-specific promoter to focus on resident macrophages in the normal mouse heart.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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).This work introduces cardiac macrophage subsets in the mouse and describes their origins.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    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).

    CAS  PubMed  Google Scholar 

  16. 16.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).This work confirms that most human cardiac macrophages, as in the mouse, do not derive from circulating monocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Choi, J. H. et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J. Exp. Med. 206, 497–505 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

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

    CAS  PubMed  Google Scholar 

  20. 20.

    Ito, B. R., Engler, R. L. & del Balzo, U. Role of cardiac mast cells in complement C5a-induced myocardial ischemia. Am. J. Physiol. 264, H1346–H1354 (1993).

    CAS  PubMed  Google Scholar 

  21. 21.

    Ngkelo, A. et al. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction. J. Exp. Med. 213, 1353–1374 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Patella, V. et al. Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. J. Immunol. 154, 2855–2865 (1995).

    CAS  PubMed  Google Scholar 

  23. 23.

    Leid, J. et al. Primitive embryonic macrophages are required for coronary development and maturation. Circ. Res. 118, 1498–1511 (2016).This study suggests that macrophages are involved in cardiac development.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Butts, B. et al. Increased inflammation in pericardial fluid persists 48 hours after cardiac surgery. Circulation 136, 2284–2286 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Horckmans, M. et al. Pericardial adipose tissue regulates granulopoiesis, fibrosis, and cardiac function after myocardial infarction. Circulation 137, 948–960 (2018).

    PubMed  Google Scholar 

  27. 27.

    Wang, J. & Kubes, P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165, 668–678 (2016).

    CAS  PubMed  Google Scholar 

  28. 28.

    Weber, G. F. et al. Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J. Exp. Med. 211, 1243–1256 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Gwechenberger, M. et al. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation 99, 546–551 (1999).

    CAS  PubMed  Google Scholar 

  30. 30.

    Wu, L. et al. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J. Exp. Med. 211, 1449–1464 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bach, L. A. Endothelial cells and the IGF system. J. Mol. Endocrinol. 54, R1–R13 (2015).

    CAS  PubMed  Google Scholar 

  35. 35.

    Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018).

    CAS  PubMed  Google Scholar 

  36. 36.

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

    PubMed  Google Scholar 

  37. 37.

    Palmer, D. B. The effect of age on thymic function. Front. Immunol. 4, 316 (2013).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Rea, I. M. et al. Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol. 9, 586 (2018).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

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

    CAS  PubMed  Google Scholar 

  40. 40.

    Swirski, F. K. Inflammation and CVD in 2017: from clonal haematopoiesis to the CANTOS trial. Nat. Rev. Cardiol. 15, 79–80 (2018).

    PubMed  Google Scholar 

  41. 41.

    Chen, W. & Frangogiannis, N. G. The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev. 15, 415–422 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Loffredo, F. S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Smith, S. C. et al. GDF11 does not rescue aging-related pathological hypertrophy. Circ. Res. 117, 926–932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Frangogiannis, N. G. Chemokines in the ischemic myocardium: from inflammation to fibrosis. Inflamm Res. 53, 585–595 (2004).

    CAS  PubMed  Google Scholar 

  45. 45.

    Frangogiannis, N. G. et al. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation 115, 584–592 (2007).

    CAS  PubMed  Google Scholar 

  46. 46.

    Swirski, F. K. & Nahrendorf, M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339, 161–166 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Dewald, O. et al. CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ. Res. 96, 881–889 (2005).This work describes the importance of the chemokine CCL2 in the response to myocardial infarction.

    CAS  PubMed  Google Scholar 

  49. 49.

    Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity 34, 590–601 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Berg, K. E. et al. Elevated CD14++CD16- monocytes predict cardiovascular events. Circ. Cardiovasc. Genet. 5, 122–131 (2012).

    CAS  PubMed  Google Scholar 

  52. 52.

    Coller, B. S. Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene? Arterioscler Thromb. Vasc. Biol. 25, 658–670 (2005).

    CAS  PubMed  Google Scholar 

  53. 53.

    Rogacev, K. S. et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J. Am. Coll. Cardiol. 60, 1512–1520 (2012).

    CAS  PubMed  Google Scholar 

  54. 54.

    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).

    CAS  PubMed  Google Scholar 

  55. 55.

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

    CAS  PubMed  Google Scholar 

  56. 56.

    Frangogiannis, N. G., Smith, C. W. & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovasc. Res. 53, 31–47 (2002).

    CAS  PubMed  Google Scholar 

  57. 57.

    Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Krishnamurthy, P. et al. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ. Res. 104, e9–e18 (2009).

    CAS  PubMed  Google Scholar 

  60. 60.

    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).

    CAS  PubMed  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Weirather, J. et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ. Res. 115, 55–67 (2014).

    CAS  PubMed  Google Scholar 

  63. 63.

    Korf-Klingebiel, M. et al. Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat. Med. 21, 140–149 (2015).

    CAS  PubMed  Google Scholar 

  64. 64.

    Panizzi, P. et al. Impaired infarct healing in atherosclerotic mice with Ly-6Chi monocytosis. J. Am. Coll. Cardiol. 55, 1629–1638 (2010).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    van Amerongen, M. J., Harmsen, M. C., van Rooijen, N., Petersen, A. H. & van Luyn, M. J. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol. 170, 818–829 (2007).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    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).

    PubMed  Google Scholar 

  67. 67.

    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).

    PubMed  Google Scholar 

  68. 68.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Ismahil, M. A. et al. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ. Res. 114, 266–282 (2014).This manuscript elucidates the role of the spleen in the progression of heart failure in mice.

    CAS  PubMed  Google Scholar 

  70. 70.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Bansal, S. S. et al. Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ. Heart Fail. 10, e003688 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Engstrom, G., Melander, O. & Hedblad, B. Leukocyte count and incidence of hospitalizations due to heart failure. Circ. Heart Fail. 2, 217–222 (2009).

    PubMed  Google Scholar 

  73. 73.

    Moslehi, J. J., Salem, J. E., Sosman, J. A., Lebrun-Vignes, B. & Johnson, D. B. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 391, 933 (2018).

    PubMed  Google Scholar 

  74. 74.

    Braunwald, E. Cardiomyopathies: an overview. Circ. Res. 121, 711–721 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Cooper, L. T. J. Myocarditis. N. Engl. J. Med. 360, 1526–1538 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Cihakova, D. & Rose, N. R. Pathogenesis of myocarditis and dilated cardiomyopathy. Adv. Immunol. 99, 95–114 (2008).

    CAS  PubMed  Google Scholar 

  77. 77.

    Coyne, C. B. & Bergelson, J. M. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119–131 (2006).

    CAS  PubMed  Google Scholar 

  78. 78.

    Fairweather, D. et al. Mast cells and innate cytokines are associated with susceptibility to autoimmune heart disease following coxsackievirus B3 infection. Autoimmunity 37, 131–145 (2004).

    CAS  PubMed  Google Scholar 

  79. 79.

    Fairweather, D. et al. IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. J. Immunol. 174, 261–269 (2005).

    CAS  PubMed  Google Scholar 

  80. 80.

    Fuse, K. et al. Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation 112, 2276–2285 (2005).

    CAS  PubMed  Google Scholar 

  81. 81.

    Holm, G. H. et al. Interferon regulatory factor 3 attenuates reovirus myocarditis and contributes to viral clearance. J. Virol. 84, 6900–6908 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Riad, A. et al. Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo. Am. J. Physiol. Heart Circ. Physiol. 298, H2024–H2031 (2010).

    CAS  PubMed  Google Scholar 

  83. 83.

    Valaperti, A. et al. Innate immune interleukin-1 receptor-associated kinase 4 exacerbates viral myocarditis by reducing CCR5+ CD11b+ monocyte migration and impairing interferon production. Circulation 128, 1542–1554 (2013).

    CAS  PubMed  Google Scholar 

  84. 84.

    Clemente-Casares, X. et al. A CD103+ conventional dendritic cell surveillance system prevents development of overt heart failure during subclinical viral myocarditis. Immunity 47, 974–989 (2017).

    CAS  PubMed  Google Scholar 

  85. 85.

    Liu, P. et al. The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat. Med. 6, 429–434 (2000).

    CAS  PubMed  Google Scholar 

  86. 86.

    Baldeviano, G. C. et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ. Res. 106, 1646–1655 (2010).

    CAS  PubMed  Google Scholar 

  87. 87.

    Nindl, V. et al. Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. Eur. J. Immunol. 42, 2311–2321 (2012).

    CAS  PubMed  Google Scholar 

  88. 88.

    Shi, Y. et al. Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway. Circulation 121, 2624–2634 (2010).

    CAS  PubMed  Google Scholar 

  89. 89.

    Frisancho-Kiss, S. et al. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J. Immunol. 178, 6710–6714 (2007).

    CAS  PubMed  Google Scholar 

  90. 90.

    Li, Y., Heuser, J. S., Cunningham, L. C., Kosanke, S. D. & Cunningham, M. W. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J. Immunol. 177, 8234–8240 (2006).

    CAS  PubMed  Google Scholar 

  91. 91.

    Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat. Med. 9, 1484–1490 (2003).

    CAS  PubMed  Google Scholar 

  92. 92.

    Kaya, Z., Leib, C. & Katus, H. A. Autoantibodies in heart failure and cardiac dysfunction. Circ. Res. 110, 145–158 (2012).

    CAS  PubMed  Google Scholar 

  93. 93.

    Diny, N. L. et al. Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy. J. Exp. Med. 214, 943–957 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Paulus, W. J. et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the heart failure and echocardiography associations of the european society of cardiology. Eur. Heart J. 28, 2539–2550 (2007).

    PubMed  Google Scholar 

  95. 95.

    Sharma, K. & Kass, D. A. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ. Res. 115, 79–96 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Laroumanie, F. et al. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation 129, 2111–2124 (2014).

    CAS  PubMed  Google Scholar 

  97. 97.

    Nevers, T. et al. Left ventricular T cell recruitment contributes to the pathogenesis of heart failure. Circ. Heart Fail. 8, 776–787 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Nevers, T. et al. Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J. Exp. Med. 214, 3311–3329 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Glezeva, N. et al. Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis. J. Card Fail. 21, 167–177 (2015).

    CAS  PubMed  Google Scholar 

  100. 100.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Pinto, A. R., Godwin, J. W. & Rosenthal, N. A. Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res. 13, 705–714 (2014).

    CAS  PubMed  Google Scholar 

  102. 102.

    Holland, T. L. et al. Infective endocarditis. Nat. Rev. Dis. Primers. 2, 16059 (2016).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Thammavongsa, V., Kim, H. K., Missiakas, D. & Schneewind, O. Staphylococcal manipulation of host immune responses. Nat. Rev. Microbiol. 13, 529–543 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Feuerstein, R., Seidl, M., Prinz, M. & Henneke, P. MyD88 in macrophages is critical for abscess resolution in staphylococcal skin infection. J. Immunol. 194, 2735–2745 (2015).

    CAS  PubMed  Google Scholar 

  105. 105.

    Veltrop, M. H., Bancsi, M. J., Bertina, R. M. & Thompson, J. Role of monocytes in experimental Staphylococcus aureus endocarditis. Infect. Immun. 68, 4818–4821 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Friedrich, R. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425, 535–539 (2003).

    CAS  PubMed  Google Scholar 

  107. 107.

    Shahreyar, M. et al. Severe sepsis and cardiac arrhythmias. Ann. Transl Med. 6, 6 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Moss, T. J. et al. New-onset atrial fibrillation in the critically ill. Crit. Care Med. 45, 790–797 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Lazzerini, P. E., Capecchi, P. L. & Laghi-Pasini, F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur. Heart J. 38, 1717–1727 (2017).

    CAS  PubMed  Google Scholar 

  110. 110.

    Abdelhadi, R. H., Gurm, H. S., Van Wagoner, D. R. & Chung, M. K. Relation of an exaggerated rise in white blood cells after coronary bypass or cardiac valve surgery to development of atrial fibrillation postoperatively. Am. J. Cardiol. 93, 1176–1178 (2004).

    PubMed  Google Scholar 

  111. 111.

    Guo, Y., Lip, G. Y. & Apostolakis, S. Inflammation in atrial fibrillation. J. Am. Coll. Cardiol. 60, 2263–2270 (2012).

    CAS  PubMed  Google Scholar 

  112. 112.

    Chen, M. C. et al. Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation. Am. J. Cardiol. 102, 861–865 (2008).

    PubMed  Google Scholar 

  113. 113.

    Smorodinova, N. et al. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLOS ONE 12, e0172691 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Yue, L., Xie, J. & Nattel, S. Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc. Res. 89, 744–753 (2011).

    CAS  PubMed  Google Scholar 

  115. 115.

    Sun, Z. et al. Cross-talk between macrophages and atrial myocytes in atrial fibrillation. Bas. Res. Cardiol. 111, 63 (2016).

    Google Scholar 

  116. 116.

    Riley, G., Syeda, F., Kirchhof, P. & Fabritz, L. An introduction to murine models of atrial fibrillation. Front. Physiol. 3, 296 (2012).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    De Jesus, N. M. et al. Atherosclerosis exacerbates arrhythmia following myocardial infarction: role of myocardial inflammation. Heart Rhythm. 12, 169–178 (2015).

    PubMed  Google Scholar 

  118. 118.

    De Jesus, N. M. et al. Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm. 14, 727–736 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Monnerat, G. et al. Macrophage-dependent IL-1beta production induces cardiac arrhythmias in diabetic mice. Nat. Commun. 7, 13344 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Mann, D. L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988–998 (2002).

    CAS  PubMed  Google Scholar 

  121. 121.

    Meier, L. A. et al. CD301b/MGL2+ mononuclear phagocytes orchestrate autoimmune cardiac valve inflammation and fibrosis. Circulation 137, 2478–2493 (2018).

    CAS  PubMed  Google Scholar 

  122. 122.

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

    CAS  Google Scholar 

  123. 123.

    Johnson, D. B. et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375, 1749–1755 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Okazaki, T. et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat. Med. 9, 1477–1483 (2003).

    CAS  PubMed  Google Scholar 

  125. 125.

    Rudolph, V. et al. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat. Med. 16, 470–474 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Stanek, G., Wormser, G. P., Gray, J. & Strle, F. Lyme borreliosis. Lancet 379, 461–473 (2012).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge K. Joyes for editing the manuscript. This work was funded in part by federal funds from the US National Heart, Lung, and Blood Institute (NHLBI) (HL135752 and HL139598) and the Massachusetts General Hospital Research Scholar Program.

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Nature Reviews Immunology thanks D. Ciháková, S. Epelman and J.-S. Silvestre for their contribution to the peer review of this work.

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Both authors researched data for the article, discussed its content and wrote, reviewed and edited the article.

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Correspondence to Filip K. Swirski or Matthias Nahrendorf.

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Glossary

Cardiomyocytes

Large muscle cells specific to the heart.

Definitive haematopoiesis

The production of mature blood cells from haematopoietic progenitor cells in the bone marrow that occurs throughout life.

Atrioventricular node

The node that controls the ventricular heart rate and is a major relay station for electrical conduction from atria to ventricles in the heart.

Pericardium

The membrane layer enclosing the heart.

Serosal fluid

Fluid in body cavities such as the pericardium.

Primitive coronary plexus

A developmental stage of the coronary vasculature.

Gap junctions

Intercellular connections formed by connexin proteins that directly connect the cytoplasm of two cells and enable exchange of ions, which electrically couples cardiomyocytes to each other and to macrophages.

Source–sink relationship

An interaction that involves the exchange of charges between excitable cardiomyocytes and passively depolarized macrophages.

Optical tissue clearance

A method by which biological specimens are treated to enable whole organ microscopy.

Sinus node

The pacemaker of the heart, consisting of a cluster of spontaneously depolarizing cells in which electrical impulses are generated.

CD11b DTR mice

Transgenic mice expressing the diphtheria toxin receptor under control of the Cd11b (also known as Itgam) gene promoter, which enables macrophage depletion after injection of non-toxic doses of diphtheria toxin.

Granulation tissue

Newly forming tissue during wound healing that contains leukocytes, stromal cells, extracellular matrix and blood vessels.

Non-reperfused myocardial infarction

An event that occurs when a coronary artery is closed off and not re-opened for blood flow, leading to the ischaemic death of a large number of cardiac cells.

Remote myocardium

The part of the heart that is not directly affected by ischaemia during myocardial infarction.

Ejection fraction

The volume of blood ejected with each heartbeat, which is normalized to the size of the left ventricular cavity.

Sympathetic tone

Innervation by a branch of the autonomous nervous system that increases the output of the heart but also has many other functions, including in the haematopoietic and immune systems.

Dilated cardiomyopathy

Enlargement of the left ventricle leading to heart failure.

Re-entry arrhythmias

Conduction disorders in which the depolarizing wave front circles, often leading to rapid and uncoordinated cardiomyocyte contractions.

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Swirski, F.K., Nahrendorf, M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat Rev Immunol 18, 733–744 (2018). https://doi.org/10.1038/s41577-018-0065-8

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