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  • Review Article
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Innate immune signaling in cardiac ischemia

Abstract

Despite advances in treatment of patients who suffer from ischemic heart disease, morbidity related to myocardial infarction is increasing in Western societies. Acute and chronic immune responses elicited by myocardial ischemia have an important role in the functional deterioration of the heart. Research on modulation of the inflammatory responses was focused on effector mediators such as leukocytes. However, increasing evidence indicates that various endogenous ligands that act as 'danger signals', also called danger-associated molecular patterns (DAMPs), are released upon injury and modulate inflammation. Originally described as part of the first-line defense against invading microorganisms, several Toll-like receptors (TLRs) on leukocytes and parenchymal cells have now been shown to respond to such signals and to have a pivotal role in noninfectious pathological cardiovascular conditions, such as ischemia–reperfusion injury and heart failure. From a therapeutic perspective, DAMPs are attractive targets owing to their specific induction after injury. In this Review, we will discuss innate immune activation through TLRs in cardiac ischemia mediated by DAMPs.

Key Points

  • Innate immune responses are critical mediators of tissue damage and repair after myocardial infarction

  • Cells involved in innate immunity also recognize and become activated by molecules released after cell death or by matrix degradation products, so-called 'danger signals' or danger-associated molecular patterns (DAMPs)

  • Toll-like receptors on cardiac and circulating cells recognize pathogen-associated molecular patterns as well as DAMPs and are important mediators of inflammatory reactions after cardiac ischemia

  • Preclinical studies show that DAMPs are promising targets to enhance myocardial viability and repair after myocardial infarction

  • As several DAMPs are necessary for proper wound healing, therapeutic interference with DAMP-related signaling in patients after myocardial infarction necessitates careful evaluation and further research

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Figure 1: TLR signaling.
Figure 2: The role of DAMPs in myocardial ischemia–reperfusion injury.
Figure 3: The role of DAMPs in cardiac remodeling.
Figure 4: Divergent HMGB1-mediated responses after ischemia.

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References

  1. Virchow, R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI—Atheromatous affection of arteries. 1858. Nutr. Rev. 47, 23–25 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Van, A. W. I. Landerer's mechanical theory of inflammation. Ann. Surg. 2, 479–485 (1885).

    Article  Google Scholar 

  3. Lefer, A. M. & Rovetto, M. J. Influence of a myocardial depressant factor on physiologic properties of cardiac muscle. Proc. Soc. Exp. Biol. Med. 134, 269–273 (1970).

    Article  CAS  PubMed  Google Scholar 

  4. Lefer, A. M., Cowgill, R., Marshall, F. F., Hall, L. M. & Brand, E. D. Characterization of a myocardial depressant factor present in hemorrhagic shock. Am. J. Physiol. 213, 492–498 (1967).

    Article  CAS  PubMed  Google Scholar 

  5. Brand, E. D. & Lefer, A. M. Myocardial depressant factor in plasma from cats in irreversible post-oligemic shock. Proc. Soc. Exp. Biol. Med. 122, 200–203 (1966).

    Article  CAS  PubMed  Google Scholar 

  6. Arslan, F., de Kleijn, D. P., Timmers, L., Doevendans, P. A. & Pasterkamp, G. Bridging innate immunity and myocardial ischemia/reperfusion injury: the search for therapeutic targets. Curr. Pharm. Des. 14, 1205–1216 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Chao, W. Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. Am. J. Physiol. Heart Circ. Physiol. 296, H1–12 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Kelly, R. A. & Smith, T. W. Cytokines and cardiac contractile function. Circulation 95, 778–781 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Frangogiannis, N. G. The immune system and cardiac repair. Pharmacol. Res. 58, 88–111 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rezkalla, S. H. & Kloner, R. A. Coronary no-reflow phenomenon: from the experimental laboratory to the cardiac catheterization laboratory. Catheter. Cardiovasc. Interv. 72, 950–957 (2008).

    Article  PubMed  Google Scholar 

  13. Vinten-Johansen, J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc. Res. 61, 481–497 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Dobaczewski, M., Gonzalez-Quesada, C. & Frangogiannis, N. G. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J. Mol. Cell Cardiol. 48, 504–511 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Spinale, F. G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285–1342 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat. Rev. Immunol. 4, 469–478 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Ionita, M. G., Arslan, F., de Kleijn, D. P. & Pasterkamp, G. Endogenous inflammatory molecules engage Toll-like receptors in cardiovascular disease. J. Innate. Immun. 2, 307–315 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Blasius, A. L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305–315 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Hansson, G. K. Immune and inflammatory mechanisms in the development of atherosclerosis. Br. Heart J. 69, S38–S41 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brodison, A. & Swann, J. W. Myocarditis: a review. J. Infect. 37, 99–103 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Hansson, G. K. & Edfeldt, K. Toll to be paid at the gateway to the vessel wall. Arterioscler. Thromb. Vasc. Biol. 25, 1085–1087 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Li, M., Zhou, Y., Feng, G. & Su, S. B. The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Curr. Mol. Med. 9, 365–374 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Frantz, S., Ertl, G. & Bauersachs, J. Toll-like receptor signaling in the ischemic heart. Front. Biosci. 13, 5772–5779 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Kumar, H., Kawai, T. & Akira, S. Toll-like receptors and innate immunity. Biochem. Biophys. Res. Commun. 388, 621–625 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Arslan, F., Keogh, B., McGuirk, P. & Parker, A. E. TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm. doi:10.1155/2010/704202.

    Article  CAS  Google Scholar 

  29. Favre, J. et al. Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction. Arterioscler. Thromb. Vasc. Biol. 27, 1064–1071 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Knuefermann, P. et al. Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart. Circulation 110, 3693–3698 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Boyd, J. H., Mathur, S., Wang, Y., Bateman, R. M. & Walley, K. R. Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. Cardiovasc. Res. 72, 384–393 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Sakata, Y. et al. Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 292, H503–H509 (2007).

    Article  CAS  Google Scholar 

  33. Landmesser, U., Wollert, K. C. & Drexler, H. Potential novel pharmacological therapies for myocardial remodelling. Cardiovasc. Res. 81, 519–527 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Cohn, J. N., Ferrari, R. & Sharpe, N. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J. Am. Coll. Cardiol. 35, 569–582 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Shishido, T. et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 108, 2905–2910 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Timmers, L. et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ. Res. 102, 257–264 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Satoh, M. et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction. Int. J. Cardiol. 109, 226–234 (2006).

    Article  PubMed  Google Scholar 

  38. Timmers, L. et al. Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ. Res. 104, 699–706 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Piper, H. M., Abdallah, Y. & Schafer, C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc. Res. 61, 365–371 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Eefting, F. et al. Role of apoptosis in reperfusion injury. Cardiovasc. Res. 61, 414–426 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Inserte, J., Barrabes, J. A., Hernando, V. & Garcia-Dorado, D. Orphan targets for reperfusion injury. Cardiovasc. Res. 83, 169–178 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Gustafsson, A. B. & Gottlieb, R. A. Heart mitochondria: gates of life and death. Cardiovasc. Res. 77, 334–343 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Garrido, C., Gurbuxani, S., Ravagnan, L. & Kroemer, G. Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem. Biophys. Res. Commun. 286, 433–442 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Kol, A., Lichtman, A. H., Finberg, R. W., Libby, P. & Kurt-Jones, E. A. Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J. Immunol. 164, 13–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Tissieres, A., Mitchell, H. K. & Tracy, U. M. Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J. Mol. Biol. 84, 389–398 (1974).

    Article  CAS  PubMed  Google Scholar 

  47. Young, J. C. Mechanisms of the Hsp70 chaperone system. Biochem. Cell. Biol. 88, 291–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Daugaard, M., Rohde, M. & Jaattela, M. The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett. 581, 3702–3710 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Currie, R. W. & White, F. P. Trauma-induced protein in rat tissues: a physiological role for a “heat shock” protein? Science 214, 72–73 (1981).

    Article  CAS  PubMed  Google Scholar 

  50. Currie, R. W. Effects of ischemia and perfusion temperature on the synthesis of stress-induced (heat shock) proteins in isolated and perfused rat hearts. J. Mol. Cell Cardiol. 19, 795–808 (1987).

    Article  CAS  PubMed  Google Scholar 

  51. Yellon, D. M. & Latchman, D. S. Stress proteins and myocardial protection. J. Mol. Cell Cardiol. 24, 113–124 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Gupta, M., Vavasis, C. & Frishman, W. H. Heat shock proteins in cardiovascular disease a new therapeutic target. Cardiol. Rev. 12, 26–30 (2004).

    Article  PubMed  Google Scholar 

  53. Fan, G. C., Chu, G. & Kranias, E. G. Hsp20 and its cardioprotection. Trends Cardiovasc. Med. 15, 138–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Tanonaka, K., Yoshida, H., Toga, W., Furuhama, K. & Takeo, S. Myocardial heat shock proteins during the development of heart failure. Biochem. Biophys. Res. Commun. 283, 520–525 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Knowlton, A. A. et al. Differential expression of heat shock proteins in normal and failing human hearts. J. Mol. Cell Cardiol. 30, 811–818 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Yellon, D. M. et al. Whole body heat stress fails to limit infarct size in the reperfused rabbit heart. Cardiovasc. Res. 26, 342–346 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Legare, J. F., Oxner, A., Heimrath, O., Myers, T. & Currie, R. W. Heat shock treatment results in increased recruitment of labeled PMN following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 293, H3210–H3215 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Zal, B. et al. Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. Circulation 109, 1230–1235 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Lin, L. et al. HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis. Am. J. Physiol. Heart Circ. Physiol. 293, H2238–H2247 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, S. C. et al. Extracellular heat shock protein 60, cardiac myocytes, and apoptosis. Circ. Res. 105, 1186–1195 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Olivetti, G. et al. Apoptosis in the failing human heart. N. Engl. J. Med. 336, 1131–1141 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Sharma, A. K., Dhingra, S., Khaper, N. & Singal, P. K. Activation of apoptotic processes during transition from hypertrophy to heart failure in guinea pigs. Am. J. Physiol. Heart Circ. Physiol. 293, H1384–H1390 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Dorn, G. W. Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc. Res. 81, 465–473 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Park, M. et al. Apoptosis predominates in nonmyocytes in heart failure. Am. J. Physiol. Heart Circ. Physiol. 297, H785–H791 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Muller, S., Ronfani, L. & Bianchi, M. E. Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J. Intern. Med. 255, 332–343 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat. Rev. Immunol. 5, 331–342 (2005).

    CAS  PubMed  Google Scholar 

  69. Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rendon-Mitchell, B. et al. IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism. J. Immunol. 170, 3890–3897 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Chen, G. et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through. J. Leukoc. Biol. 76, 994–1001 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Li, W., Sama, A. E. & Wang, H. Role of HMGB1 in cardiovascular diseases. Curr. Opin. Pharmacol. 6, 130–135 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Park, J. S. et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370–7377 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Ivanov, S. et al. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110, 1970–1981 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8, 487–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Kohno, T. et al. Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling. Cardiovasc. Res. 81, 565–573 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Takahashi, K. et al. Modulated inflammation by injection of high-mobility group box 1 recovers post-infarction chronically failing heart. Circulation 118, S106–S114 (2008).

    PubMed  Google Scholar 

  78. Goldstein, R. S. et al. Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. Shock 25, 571–574 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Kitahara, T. et al. High-mobility group box 1 restores cardiac function after myocardial infarction in transgenic mice. Cardiovasc. Res. 80, 40–46 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Limana, F. et al. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ. Res. 97, e73–e83 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Rossini, A. et al. HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells. J. Mol. Cell Cardiol. 44, 683–693 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Andrassy, M. et al. High-mobility group Box-1 in ischemia-reperfusion injury of the heart. Circulation 117, 3216–3226 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Tzeng, H. P. et al. Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 294, H1490–H1496 (2008).

    Article  CAS  Google Scholar 

  84. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Natanson, C. et al. Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J. Clin. Invest. 83, 243–251 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ono, M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci. 99, 1501–1506 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. vid Dong, Z. M., Aplin, A. C. & Nicosia, R. F. Regulation of angiogenesis by macrophages, dendritic cells, and circulating myelomonocytic cells. Curr. Pharm. Des. 15, 365–379 (2009).

    Article  Google Scholar 

  89. Srikrishna, G. & Freeze, H. H. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia 11, 615–628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sharma, A., Ray, R. & Rajeswari, M. R. Overexpression of high mobility group (HMG) B1 and B2 proteins directly correlates with the progression of squamous cell carcinoma in skin. Cancer Invest. 26, 843–851 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Dobaczewski, M. et al. Extracellular matrix remodeling in canine and mouse myocardial infarcts. Cell Tissue Res. 324, 475–488 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Comper, W. D. & Laurent, T. C. Physiological function of connective tissue polysaccharides. Physiol. Rev. 58, 255–315 (1978).

    Article  CAS  PubMed  Google Scholar 

  93. Waldenstrom, A., Martinussen, H. J., Gerdin, B. & Hallgren, R. Accumulation of hyaluronan and tissue edema in experimental myocardial infarction. J. Clin. Invest. 88, 1622–1628 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Termeer, C. et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Gariboldi, S. et al. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J. Immunol. 181, 2103–2110 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11, 1173–1179 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Zheng, L., Riehl, T. E. & Stenson, W. F. Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology 137, 2041–2051 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Liao, Y. F., Gotwals, P. J., Koteliansky, V. E., Sheppard, D. & Van De, W. L. The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J. Biol. Chem. 277, 14467–14474 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Schoneveld, A. H. et al. Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness. Atherosclerosis 197, 95–104 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Arslan, F. et al. Lack of fibronectin-EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction. Circ. Res. 108, 582–592 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Fairweather, D. et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J. Immunol. 176, 3516–3524 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Zhang, P., Cox, C. J., Alvarez, K. M. & Cunningham, M. W. Cutting edge: cardiac myosin activates innate immune responses through TLRs. J. Immunol. 183, 27–31 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Erridge, C. & Samani, N. J. Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler. Thromb. Vasc. Biol. 29, 1944–1949 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Tsan, M. F. & Gao, B. Endogenous ligands of Toll-like receptors. J. Leukoc. Biol. 76, 514–519 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Tsan, M. F. & Baochong, G. Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J. Endotoxin. Res. 13, 6–14 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Zhu, X. et al. Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Crit. Care Med. 35, 886–892 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Schoneveld, A. H. et al. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc. Res. 66, 162–169 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Bjorkbacka, H. Multiple roles of Toll-like receptor signaling in atherosclerosis. Curr. Opin. Lipidol. 17, 527–533 (2006).

    Article  PubMed  CAS  Google Scholar 

  111. Hardarson, H. S. et al. Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury. Am. J. Physiol. Heart Circ. Physiol. 292, H251–H258 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Richer, M. J., Lavallee, D. J., Shanina, I. & Horwitz, M. S. Toll-like receptor 3 signaling on macrophages is required for survival following coxsackievirus B4 infection. PLoS One 4, e4127 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  114. Fairweather, D. et al. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J. Immunol. 170, 4731–4737 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Vink, A. et al. In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation 106, 1985–1990 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Triantafilou, K. et al. Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol. 7, 1117–1126 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Yu, Q. et al. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am. J. Physiol. Heart Circ. Physiol. 297, H76–H85 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bulicheva, N. et al. Effect of cell-free DNA of patients with cardiomyopathy and rDNA on the frequency of contraction of electrically paced neonatal rat ventricular myocytes in culture. Ann. N. Y. Acad. Sci. 1137, 273–277 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Knuefermann, P. et al. Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of toll-like receptor 9. Cardiovasc. Res. 78, 26–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Chen, L. et al. TLR signals promote IL-6/IL-17-dependent transplant rejection. J. Immunol. 182, 6217–6225 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Professor N. G. Frangogiannis for his critical review of the manuscript. This work is supported by research grants from The Netherlands Organization for Scientific Research and Utrecht University Mozaïek grant (contract 017.004.004 to F. Arslan) and Netherlands Heart Foundation (contract 2010T001 to F. Arslan).

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F. Arslan researched data and wrote the manuscript. G. Pasterkamp and D. P. de Kleijn reviewed and edited the article before submission.

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Correspondence to Dominique P. de Kleijn.

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Arslan, F., de Kleijn, D. & Pasterkamp, G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol 8, 292–300 (2011). https://doi.org/10.1038/nrcardio.2011.38

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