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Role of innate and adaptive immune mechanisms in cardiac injury and repair

Nature Reviews Immunology volume 15, pages 117–129 (2015)Cite this article

Subjects

Key Points

  • Cardiac injury can lead to cardiomyocyte death, intense inflammation, scar formation and, over time, adverse cardiac remodelling.

  • Following injury, cardiac inflammation is triggered by the release of conserved endogenous molecules and the production of pro-inflammatory cytokines and chemokines that lead to cellular infiltration.

  • Early activation of mast cells leads to neutrophil recruitment, a robust inflammatory response and tissue damage.

  • Recruited monocytes and resident macrophages modulate both tissue injury and tissue healing.

  • Macrophage origin may dictate function in the heart. Primitive embryonically derived macrophages mediate cardiac tissue repair, whereas bone marrow-derived monocytes contribute to inflammation following cardiac injury.

  • Lymphocytes and macrophages are involved in the complex transition from initial cardiac tissue inflammation to wound healing.

Abstract

Despite the advances that have been made in developing new therapeutics, cardiovascular disease remains the leading cause of worldwide mortality. Therefore, understanding the mechanisms underlying cardiovascular tissue injury and repair is of prime importance. Following cardiac tissue injury, the immune system has an important and complex role in driving both the acute inflammatory response and the regenerative response. This Review summarizes the role of the immune system in cardiovascular disease — focusing on the idea that the immune system evolved to promote tissue homeostasis following injury and/or infection, and that the inherent cost of this evolutionary development is unwanted inflammatory damage.

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Figure 1: Immune cells in the resting heart.
Figure 2: Cardiac injury and sensing damaged tissue.
Figure 3: Immune response to ischaemic injury in adult animals.
Figure 4: Role of embryonically derived macrophages during tissue injury and repair.
Figure 5: Interaction of coxsackievirus B with the host innate and acquired immune system.

References

  1. Ma, X., Cong, P., Hou, X., Edgecombe, G. D. & Strausfeld, N. J. An exceptionally preserved arthropod cardiovascular system from the early Cambrian. Nature Commun. 5, 3560 (2014).

    Google Scholar 

  2. Bier, E. & Bodmer, R. Drosophila, an emerging model for cardiac disease. Gene 342, 1–11 (2004).

    CAS  PubMed  Google Scholar 

  3. Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).

    PubMed  Google Scholar 

  4. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 is the first study to show that cardiac macrophages are not a single population but are composed of distinct subsets, with different origins and functions.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007). This report shows the initial characterization of cardiac macrophages in the resting heart and after ischaemic injury.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. 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 

  9. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. 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 

  12. Roger, V. L. et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125, e2–e220 (2012).

    PubMed  Google Scholar 

  13. Jacoby, D. & McKenna, W. J. Genetics of inherited cardiomyopathy. Eur. Heart J. 33, 296–304 (2012).

    CAS  PubMed  Google Scholar 

  14. Sangiuliano, B., Perez, N. M., Moreira, D. F. & Belizario, J. E. Cell death-associated molecular-pattern molecules: inflammatory signaling and control. Mediators Inflamm. 2014, 821043 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    CAS  PubMed  Google Scholar 

  16. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54 Pt. 1, 1–13 (1989).

    CAS  PubMed  Google Scholar 

  17. Mann, D. L., Topkara, V. K., Evans, S. & Barger, P. M. Innate immunity in the adult mammalian heart: for whom the cell tolls. Trans. Am. Clin. Climatol. Assoc. 121, 34–50 (2010).

    PubMed  PubMed Central  Google Scholar 

  18. Mezzaroma, E. et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc. Natl Acad. Sci. USA 108, 19725–19730 (2011).

    CAS  PubMed  Google Scholar 

  19. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    CAS  PubMed  Google Scholar 

  20. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010).

    CAS  Google Scholar 

  21. Frantz, S. et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J. Clin. Invest. 104, 271–280 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Birks, E. J. et al. Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices. J. Heart Lung Transplant. 23, 228–235 (2004).

    PubMed  Google Scholar 

  23. Kashiwagi, M. et al. Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. Atherosclerosis 221, 249–253 (2012).

    CAS  PubMed  Google Scholar 

  24. Arslan, F. et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 121, 80–90 (2010).

    CAS  PubMed  Google Scholar 

  25. Fallach, R. et al. Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J. Mol. Cell Cardiol. 48, 1236–1244 (2010).

    CAS  PubMed  Google Scholar 

  26. Binck, B. W. et al. Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock. Am. J. Physiol. Heart Circ. Physiol. 288, H577–H583 (2005).

    CAS  PubMed  Google Scholar 

  27. Oyama, J. et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109, 784–789 (2004).

    CAS  PubMed  Google Scholar 

  28. Tavener, S. A. et al. Immune cell Toll-like receptor 4 is required for cardiac myocyte impairment during endotoxemia. Circ. Res. 95, 700–707 (2004).

    CAS  PubMed  Google Scholar 

  29. Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012). This is the first study to show that endogenous DAMPs are released from the myocardium during haemodynamic strain, a process that impairs cardiac function.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Geddes, K., Magalhaes, J. G. & Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nature Rev. Drug Discov. 8, 465–479 (2009).

    CAS  Google Scholar 

  31. Kawaguchi, M. et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123, 594–604 (2011).

    CAS  PubMed  Google Scholar 

  32. McCartney, S. A. et al. RNA sensor-induced type I IFN prevents diabetes caused by a β cell-tropic virus in mice. J. Clin. Invest. 121, 1497–1507 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Philip, J., Xu, Z., Bowles, N. E. & Vallejo, J. G. Cardiac-specific overexpression of melanoma differentiation-associated gene-5 protects mice from lethal viral myocarditis. Circ. Heart Fail. 6, 326–334 (2013).

    CAS  PubMed  Google Scholar 

  34. Lech, M. et al. Quantitative expression of C-type lectin receptors in humans and mice. Int. J. Mol. Sci. 13, 10113–10131 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Frangogiannis, N. G. & Entman, M. L. Chemokines in myocardial ischemia. Trends Cardiovasc. Med. 15, 163–169 (2005).

    CAS  PubMed  Google Scholar 

  36. Frangogiannis, N. G. The mechanistic basis of infarct healing. Antioxid. Redox. Signal. 8, 1907–1939 (2006).

    CAS  PubMed  Google Scholar 

  37. Chakraborti, T., Mandal, A., Mandal, M., Das, S. & Chakraborti, S. Complement activation in heart diseases. Role of oxidants. Cell Signal. 12, 607–617 (2000).

    CAS  PubMed  Google Scholar 

  38. Foreman, K. E., Glovsky, M. M., Warner, R. L., Horvath, S. J. & Ward, P. A. Comparative effect of C3a and C5a on adhesion molecule expression on neutrophils and endothelial cells. Inflammation 20, 1–9 (1996).

    CAS  PubMed  Google Scholar 

  39. Bhattacharya, K. et al. Mast cell deficient W/Wv mice have lower serum IL-6 and less cardiac tissue necrosis than their normal littermates following myocardial ischemia-reperfusion. Int. J. Immunopathol. Pharmacol. 20, 69–74 (2007).

    CAS  PubMed  Google Scholar 

  40. Ayach, B. B. et al. Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc. Natl Acad. Sci. USA 103, 2304–2309 (2006).

    CAS  PubMed  Google Scholar 

  41. Waskow, C., Paul, S., Haller, C., Gassmann, M. & Rodewald, H. R. Viable c-Kit(W/W) mutants reveal pivotal role for c-kit in the maintenance of lymphopoiesis. Immunity 17, 277–288 (2002).

    CAS  PubMed  Google Scholar 

  42. Dreyer, W. J. et al. Kinetics of C5a release in cardiac lymph of dogs experiencing coronary artery ischemia-reperfusion injury. Circ. Res. 71, 1518–1524 (1992).

    CAS  PubMed  Google Scholar 

  43. Newburger, P. E. & Dale, D. C. Evaluation and management of patients with isolated neutropenia. Semin. Hematol. 50, 198–206 (2013).

    PubMed  PubMed Central  Google Scholar 

  44. Singh, M. & Saini, H. K. Resident cardiac mast cells and ischemia-reperfusion injury. J. Cardiovasc. Pharmacol. Ther. 8, 135–148 (2003).

    PubMed  Google Scholar 

  45. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    CAS  PubMed  Google Scholar 

  46. Li, W. et al. Intravital 2-photon imaging of leukocyte trafficking in beating heart. J. Clin. Invest. 122, 2499–2508 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 

  48. Youker, K. et al. Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion. J. Clin. Invest. 89, 602–609 (1992). This important early study demonstrated the role of neutrophils in cardiomyocyte injury.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Entman, M. L. et al. Neutrophil induced oxidative injury of cardiac myocytes. A compartmented system requiring CD11b/CD18–ICAM-1 adherence. J. Clin. Invest. 90, 1335–1345 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Entman, M. L. et al. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism. J. Clin. Invest. 85, 1497–1506 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Tyagi, S., Klickstein, L. B. & Nicholson-Weller, A. C5a-stimulated human neutrophils use a subset of β2 integrins to support the adhesion-dependent phase of superoxide production. J. Leukoc. Biol. 68, 679–686 (2000).

    CAS  PubMed  Google Scholar 

  52. Kawakami, R. et al. Overexpression of brain natriuretic peptide facilitates neutrophil infiltration and cardiac matrix metalloproteinase-9 expression after acute myocardial infarction. Circulation 110, 3306–3312 (2004).

    CAS  PubMed  Google Scholar 

  53. Romson, J. L. et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67, 1016–1023 (1983).

    CAS  PubMed  Google Scholar 

  54. Jolly, S. R. et al. Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion. Am. Heart J. 112, 682–690 (1986).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  58. 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 

  59. 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 

  60. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 39, 599–610 (2013).

    CAS  PubMed  Google Scholar 

  62. Hanna, R. N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nature Immunol. 12, 778–785 (2011).

    CAS  Google Scholar 

  63. Hettinger, J. et al. Origin of monocytes and macrophages in a committed progenitor. Nature Immunol. 14, 821–830 (2013).

    CAS  Google Scholar 

  64. Ingersoll, M. A. et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115, e10–e19 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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). An important early study showing that CCR2 deficiency limits cardiac injury. Later studies would suggest this was due to a lack of blood monocytes.

    CAS  PubMed  Google Scholar 

  68. 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 

  69. Leuschner, F. et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ. Res. 107, 1364–1373 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009). This is the first study to show that the spleen can be a source of monocytes following cardiac injury.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 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 

  72. 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 

  73. Bracey, N. A. et al. Mitochondrial NLRP3 protein induces reactive oxygen species to promote Smad protein signaling and fibrosis independent from the inflammasome. J. Biol. Chem. 289, 19571–19584 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bracey, N. A. et al. The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1β. Exp. Physiol. 98, 462–472 (2013).

    CAS  PubMed  Google Scholar 

  75. Dunay, I. R. et al. Gr1+ inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29, 306–317 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim, Y. G. et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34, 769–780 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  80. Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotech. 29, 1005–1010 (2011).

    CAS  Google Scholar 

  81. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006).

    CAS  Google Scholar 

  82. Zhou, L. et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ. Res. 98, 1177–1185 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011). This is the first study to show that the mammalian neonatal heart can regenerate fully, similarly to what is observed in more primitive organisms.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lavine, K. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. 111, 16029–16034 (2014). This is the first study to show that resident neonatal heart macrophages, not recruited monocytes, have a key role in neonatal heart regeneration. Similar findings were seen in reference 83.

    CAS  PubMed  Google Scholar 

  86. Marodi, L. Neonatal innate immunity to infectious agents. Infect. Immun. 74, 1999–2006 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    CAS  PubMed  Google Scholar 

  88. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).

    CAS  PubMed  Google Scholar 

  89. 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 

  90. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunol. 13, 1118–1128 (2012).

    CAS  Google Scholar 

  91. Mounier, R. et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell. Metab. 18, 251–264 (2013).

    CAS  PubMed  Google Scholar 

  92. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 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 

  94. Matsumoto, K. et al. Regulatory T lymphocytes attenuate myocardial infarction-induced ventricular remodeling in mice. Int. Heart J. 52, 382–387 (2011).

    CAS  PubMed  Google Scholar 

  95. Dobaczewski, M., Xia, Y., Bujak, M., Gonzalez-Quesada, C. & Frangogiannis, N. G. CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. Am. J. Pathol. 176, 2177–2187 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang, Z. et al. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114, 2056–2064 (2006).

    CAS  PubMed  Google Scholar 

  97. Clynes, R. Protective mechanisms of IVIG. Curr. Opin. Immunol. 19, 646–651 (2007).

    CAS  PubMed  Google Scholar 

  98. Curato, C. et al. Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury. J. Immunol. 185, 6286–6293 (2010).

    CAS  PubMed  Google Scholar 

  99. Kaschina, E. et al. Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation 118, 2523–2532 (2008).

    CAS  PubMed  Google Scholar 

  100. Cohn, J. N. & Tognoni, G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N. Engl. J. Med. 345, 1667–1675 (2001).

    CAS  PubMed  Google Scholar 

  101. Dickstein, K. & Kjekshus, J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 360, 752–760 (2002).

    CAS  PubMed  Google Scholar 

  102. Mehta, P. K. & Griendling, K. K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol. 292, C82–C97 (2007).

    CAS  PubMed  Google Scholar 

  103. Bouchentouf, M. et al. Induction of cardiac angiogenesis requires killer cell lectin-like receptor 1 and α4β7 integrin expression by NK cells. J. Immunol. 185, 7014–7025 (2010).

    CAS  PubMed  Google Scholar 

  104. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    CAS  PubMed  Google Scholar 

  106. 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 

  107. Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).

    CAS  PubMed  Google Scholar 

  108. Tan, W. et al. IL-17F/IL-17R interaction stimulates granulopoiesis in mice. Exp. Hematol. 36, 1417–1427 (2008).

    CAS  PubMed  Google Scholar 

  109. Schwarzenberger, P. et al. Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis. J. Immunol. 164, 4783–4789 (2000).

    CAS  PubMed  Google Scholar 

  110. Yan, X. et al. Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction. J. Am. Heart Assoc. 1, e004408 (2012).

    PubMed  PubMed Central  Google Scholar 

  111. Liao, Y. H. et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J. Am. Coll. Cardiol. 59, 420–429 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Feng, W. et al. IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure. Exp. Mol. Pathol. 87, 212–218 (2009).

    CAS  PubMed  Google Scholar 

  113. Savvatis, K. et al. Interleukin-23 deficiency leads to impaired wound healing and adverse prognosis after myocardial infarction. Circ. Heart Fail. 7, 161–171 (2014).

    CAS  PubMed  Google Scholar 

  114. Haudek, S. B. et al. Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovasc. Res. 83, 511–518 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lim, D. S. et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103, 789–791 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Xu, J. et al. CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis. Am. J. Physiol. Heart Circ. Physiol. 301, H538–H547 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Haudek, S. B. et al. Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J. Mol. Cell Cardiol. 49, 499–507 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Sadoshima, J. & Izumo, S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ. Res. 73, 413–423 (1993).

    CAS  PubMed  Google Scholar 

  119. Marko, L. et al. Interferon-γ signaling inhibition ameliorates angiotensin II-induced cardiac damage. Hypertension 60, 1430–1436 (2012).

    CAS  PubMed  Google Scholar 

  120. Han, Y. L. et al. Reciprocal interaction between macrophages and T cells stimulates IFN-γ and MCP-1 production in Ang II-induced cardiac inflammation and fibrosis. PLoS ONE. 7, e35506 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Crawford, J. R., Haudek, S. B., Cieslik, K. A., Trial, J. & Entman, M. L. Origin of developmental precursors dictates the pathophysiologic role of cardiac fibroblasts. J. Cardiovasc. Transl. Res. 5, 749–759 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. Coura, J. R. & Borges-Pereira, J. Chagas disease: 100 years after its discovery. A systemic review. Acta Trop. 115, 5–13 (2010).

    PubMed  Google Scholar 

  123. Kindermann, I. et al. Update on myocarditis. J. Am. Coll. Cardiol. 59, 779–792 (2012).

    PubMed  Google Scholar 

  124. Neu, N. et al. Cardiac myosin induces myocarditis in genetically predisposed mice. J. Immunol. 139, 3630–3636 (1987).

    CAS  PubMed  Google Scholar 

  125. Sagar, S., Liu, P. P. & Cooper, L. T. Jr. Myocarditis. Lancet 379, 738–747 (2012).

    PubMed  Google Scholar 

  126. Kuhl, U. et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111, 887–893 (2005).

    PubMed  Google Scholar 

  127. Martino, T. A. et al. The coxsackie-adenovirus receptor (CAR) is used by reference strains and clinical isolates representing all six serotypes of coxsackievirus group B and by swine vesicular disease virus. Virology 271, 99–108 (2000).

    CAS  PubMed  Google Scholar 

  128. 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). This was the first study to show how cardiotropic viruses penetrate host epithelial barriers.

    CAS  PubMed  Google Scholar 

  129. Liu, P. P. & Opavsky, M. A. Viral myocarditis: receptors that bridge the cardiovascular with the immune system? Circ. Res. 86, 253–254 (2000).

    CAS  PubMed  Google Scholar 

  130. Kallewaard, N. L. et al. Tissue-specific deletion of the coxsackievirus and adenovirus receptor protects mice from virus-induced pancreatitis and myocarditis. Cell Host Microbe 6, 91–98 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Liu, P. et al. The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nature Med. 6, 429–434 (2000). The first study to detail the mechanisms through which cardiotropic viruses mediate intracellular signalling events and cell injury.

    CAS  PubMed  Google Scholar 

  132. Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349–354 (2001).

    CAS  PubMed  Google Scholar 

  133. 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 

  134. 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 

  135. 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 

  136. 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 

  137. Opavsky, M. A. et al. Susceptibility to myocarditis is dependent on the response of αβ T lymphocytes to coxsackieviral infection. Circ. Res. 85, 551–558 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  139. Mason, J. W. et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N. Engl. J. Med. 333, 269–275 (1995).

    CAS  PubMed  Google Scholar 

  140. Kuhl, U. et al. Interferon-β treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107, 2793–2798 (2003).

    PubMed  Google Scholar 

  141. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    CAS  PubMed  Google Scholar 

  142. Laube, F., Heister, M., Scholz, C., Borchardt, T. & Braun, T. Re-programming of newt cardiomyocytes is induced by tissue regeneration. J. Cell Sci. 119, 4719–4729 (2006).

    CAS  PubMed  Google Scholar 

  143. 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).

    CAS  PubMed  Google Scholar 

  144. Buchmann, K. Evolution of innate immunity: clues from invertebrates via fish to mammals. Front. Immunol. 5, 459 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. 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 

  146. Dai, X. M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    CAS  PubMed  Google Scholar 

  147. McKercher, S. R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl Acad. Sci. USA 87, 4828–4832 (1990).

    CAS  PubMed  Google Scholar 

  149. Nucera, S., Biziato, D. & De, P. M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int. J. Dev. Biol. 55, 495–503 (2011).

    CAS  PubMed  Google Scholar 

  150. Fantin, A. et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Arnold, T. & Betsholtz, C. The importance of microglia in the development of the vasculature in the central nervous system. Vasc. Cell 5, 4 (2013).

    PubMed  PubMed Central  Google Scholar 

  152. Lobov, I. B. et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437, 417–421 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Naqvi, N. et al. A proliferative burst during preadolescence establishes the final cardiomyocyte number. Cell 157, 795–807 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Toronto Medical Discovery Tower, 101 College Street, TMDT 3903 Toronto, Ontario, M5G 1L7, Canada

    Slava Epelman

  2. University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, K1Y 4W7, Ontario, Canada

    Peter P. Liu

  3. Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Douglas L. Mann

Authors
  1. Slava Epelman
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  2. Peter P. Liu
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  3. Douglas L. Mann
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Correspondence to Slava Epelman.

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Epelman, S., Liu, P. & Mann, D. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15, 117–129 (2015). https://doi.org/10.1038/nri3800

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