1. bookVolume 26 (2018): Issue 1 (January 2018)
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year
access type Open Access

Innate Immune Mechanisms in Myocardial Infarction - An Update

Published Online: 30 Jan 2018
Page range: 9 - 20
Received: 15 Jun 2017
Accepted: 28 Aug 2017
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year

Acute myocardial infarction (AMI) is a disease associated with high morbidity and mortality. Currently there are no available treatments specifically targeting the post-ischemic myocardial processes that lead to heart failure and recurrent coronary events. The innate immune system plays a central role in the two consecutive phases that follow an acute ischemic event: the inflammatory phase and the reparatory phase. The inflamatory phase involves a massive infiltration of neutrophils and inflammatory Ly6Chi monocytes into the injured myocardium. The reparatory phase is orchestrated by reparatory Ly6Clo macrophages that clear necrotic and apoptotic cells through efferocytosis, secrete anti-inflammatory mediators and stimulate fibrosis and repair. Important recent studies provided proof that Ly6Chi monocytes that enter the myocardium in the inflammatory phase upregulate the orphan nuclear receptor Nr4a1 and switch phenotype to Ly6CloNr4a1hi reparatory macrophages. Additionally, neutrophils have been shown to promote cardiac recovery by upregulating expression of the efferocytosis receptor MerTK on reparatory macrophages. A finely tuned balance between the inflammatory and the reparatory phases is thus essential for limiting myocardial damage and promoting efficient recovery. Treatment strategies targeting only the inflammatory phase have so far failed to improve prognosis in AMI patients. A detailed understanding of the interplay between the two phases of the innate immune response is paramount for designing efficient therapies able to improve post- AMI prognosis. In the current review, we summarize the state-of-the-art of the field and discuss previous therapeutic attempts and currently ongoing clinical trials targeting innate immune mechanisms in AMI patients.


1. Frangogiannis NG. Pathophysiology of Myocardial Infarction. Compr Physiol. 2015;5:1841-75. DOI: 10.1002/cphy.c15000610.1002/cphy.c150006Open DOISearch in Google Scholar

2. Prabhu SD, Frangogiannis NG. The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res. 2016;119:91-112. DOI: 10.1161/CIRCRESAHA.116.30357710.1161/CIRCRESAHA.116.303577Open DOISearch in Google Scholar

3. Kain V, Prabhu SD, Halade GV. Inflammation revisited: inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol. 2014;109:444. DOI: 10.1007/s00395-014-0444-710.1007/s00395-014-0444-7Open DOISearch in Google Scholar

4. Swirski FK. Inflammation and repair in the ischaemic myocardium. Hamostaseologie. 2015;35:34-6. DOI: 10.5482/HAMO-14-09-004510.5482/HAMO-14-09-0045Open DOISearch in Google Scholar

5. Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, Endo J, et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J Mol Cell Cardiol. 2013;62:24-35. DOI: 10.1016/j.yjmcc.2013.04.02310.1016/j.yjmcc.2013.04.023Open DOISearch in Google Scholar

6. Ma Y, Yabluchanskiy A, Iyer RP, Cannon PL, Flynn ER, Jung M, et al. Temporal neutrophil polarization following myocardial infarction. Cardiovasc Res. 2016;110:51-61. DOI: 10.1093/cvr/cvw02410.1093/cvr/cvw024Open DOISearch in Google Scholar

7. Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122:2711-9. DOI: 10.1172/JCI6242310.1172/JCI62423Open DOISearch in Google Scholar

8. Arslan F, de Kleijn DP and Pasterkamp G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol. 2011;8:292-300. DOI: 10.1038/nrcardio.2011.3810.1038/nrcardio.2011.38Search in Google Scholar

9. Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res. 2011;108:1133-45. DOI: 10.1161/CIRCRESAHA. 110.22693610.1161/CIRCRESAHA.110.226936Open DOISearch in Google Scholar

10. Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Extracellular heat shock protein 70 induces cardiomyocyte inflammation and contractile dysfunction via TLR2. Circ J. 2011;75:2445-52.DOI: 10.1253/circj.CJ-11-019410.1253/circj.CJ-11-0194Search in Google Scholar

11. Riva M, Kallberg E, Bjork P, Hancz D, Vogl T, Roth J, et al. Induction of nuclear factor-kappaB responses by the S100A9 protein is Toll-like receptor-4-dependent. Immunology. 2012;137:172-82. DOI: 10.1111/j.1365-2567.2012.03619.x10.1111/j.1365-2567.2012.03619.xOpen DOISearch in Google Scholar

12. Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol. 2003;170:3233-42. DOI: 10.4049/jimmunol.170.6.323310.4049/jimmunol.170.6.3233Open DOISearch in Google Scholar

13. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191-5. DOI: 10.1038/nature0085810.1038/00858Open DOISearch in Google Scholar

14. Kleinbongard P, Heusch G, Schulz R. TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 2010;127:295-314. DOI: 10.1016/j.pharmthera.2010.05.00210.1016/j.pharmthera.2010.05.002Open DOISearch in Google Scholar

15. Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, Frangogiannis NG. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. 2008;173:57-67. DOI: 10.2353/ajpath.2008.07097410.2353/ajpath.2008.070974Open DOISearch in Google Scholar

16. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc res. 2004;61:481-97. DOI: 10.1016/j.cardiores.2003.10.01110.1016/j.cardiores.2003.10.011Open DOISearch in Google Scholar

17. Carbone F, Nencioni A, Mach F, Vuilleumier N, Montecucco F. Pathophysiological role of neutrophils in acute myocardial infarction. Thromb Haemost. 2013;110:501-14. DOI: 10.1160/TH13-03-021110.1160/TH13-03-0211Open DOISearch in Google Scholar

18. Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J.2017;38:187-197.Search in Google Scholar

19. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71-82. DOI: 10.1016/ S1074-7613(03)00174-210.1016/S1074-7613(03)00174-2Open DOISearch in Google Scholar

20. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953-64. DOI: 10.1038/nri1733 10.1038/nri1733Open DOISearch in Google Scholar

21. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161-6. DOI: 10.1126/science.123071910.1126/.1230719Open DOISearch in Google Scholar

22. Wantha S, Alard JE, Megens RT, van der Does AM, Doring Y, Drechsler M, et al. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res. 2013;112:792-801. DOI: 10.1161/CIRCRESAHA.112.30066610.1161/CIRCRESAHA.112.300666Open DOISearch in Google Scholar

23. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204:3037-47.DOI: 10.1084/jem.2007088510.1084/jem.20070885Open DOISearch in Google Scholar

24. Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29:1005-10. DOI: 10.1038/nbt.198910.1038/nbt.1989Search in Google Scholar

25. Sager HB, Heidt T, Hulsmans M, Dutta P, Courties G, Sebas M, et al. Targeting Interleukin-1beta Reduces Leukocyte Production After Acute Myocardial Infarction. Circulation. 2015;132:1880-90.10.1161/CIRCULATIONAHA.115.016160Search in Google Scholar

26. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612-6. DOI: 10.1126/science.117520210.1126/.1175202Open DOISearch in Google Scholar

27. Leuschner F, Rauch PJ, Ueno T, Gorbatov R, Marinelli B, Lee WW, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012;209:123-37. DOI: 10.1084/jem.2011100910.1084/jem.20111009Open DOISearch in Google Scholar

28. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325-9. DOI: 10.1038/nature1126010.1038/11260Open DOISearch in Google Scholar

29. van der Laan AM, Ter Horst EN, Delewi R, Begieneman MP, Krijnen PA, Hirsch A, 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. 2014;35:376-85. DOI: 10.1093/eurheartj/eht33110.1093/eurheartj/eht331Open DOISearch in Google Scholar

30. Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, 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. 2009;54:130-8. DOI: 10.1016/j.jacc.2009.04.02110.1016/j.jacc.2009.04.021Search in Google Scholar

31. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792-804. DOI: 10.1016/j.immuni.2013.04.00410.1016/j.immuni.2013.04.004Open DOISearch in Google Scholar

32. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79-91. DOI: 10.1016/j.immuni.2012.12.00110.1016/j.immuni.2012.12.001Open DOISearch in Google Scholar

33. Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014;40:91-104. DOI: 10.1016/j.immuni.2013.11.01910.1016/j.immuni.2013.11.019Open DOISearch in Google Scholar

34. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392-404. DOI: 10.1038/nri367110.1038/nri3671Open DOISearch in Google Scholar

35. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt JA, et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol. 2011;12:778-85. DOI: 10.1038/ni.206310.1038/ni.2063Open DOISearch in Google Scholar

36. Hilgendorf I, Gerhardt L, Tan TC, Winter C, Holderried TA, Chousterman BG, et al. Ly-6Chigh Monocytes Depend on Nr4a1 to Balance both Inflammatory and Reparative Phases in the Infarcted Myocardium. Circ Res. 2014. DOI: 10.1161/CIRCRESAHA.114.30320410.1161/CIRCRESAHA.114.303204Open DOISearch in Google Scholar

37. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007;170:818-29. DOI: 10.2353/ajpath.2007.06054710.2353/ajpath.2007.060547Open DOISearch in Google Scholar

38. Leblond AL, Klinkert K, Martin K, Turner EC, Kumar AH, Browne T, Caplice NM. Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction. PLoS One. 2015;10:e0137515. DOI: 10.1371/journal.pone.013751510.1371/journal.pone.0137515Search in Google Scholar

39. Howangyin KY, Zlatanova I, Pinto C, Ngkelo A, Cochain C, Rouanet M, et al. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor. Circulation. 2016;133:826-39. DOI: 10.1161/CIRCULATIONAHA.115.02085710.1161/CIRCULATIONAHA.115.020857Search in Google Scholar

40. Wan E, Yeap XY, Dehn S, Terry R, Novak M, Zhang S, et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ Res. 2013;113:1004-12. DOI: 10.1161/CIRCRESAHA.113.30119810.1161/CIRCRESAHA.113.301198Open DOISearch in Google Scholar

41. Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation. 2003;108:1395-403. DOI: 10.1161/01.CIR.0000085658.98621.4910.1161/01.CIR.0000085658.98621.49Open DOISearch in Google Scholar

42. Mollmann H, Nef HM, Kostin S, von Kalle C, Pilz I, Weber M, et al. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc res. 2006;71:661-71. DOI: 10.1016/j.cardiores.2006.06.013 10.1016/j.cardiores.2006.06.013Open DOISearch in Google Scholar

43. Ruiz-Villalba A, Simon AM, Pogontke C, Castillo MI, Abizanda G, Pelacho B, et al. Interacting resident epicardium- derived fibroblasts and recruited bone marrow cells form myocardial infarction scar. J Am Coll Cardiol. 2015;65:2057-66. DOI: 10.1016/j.jacc.2015.03.52010.1016/j.jacc.2015.03.520Open DOISearch in Google Scholar

44. Yano T, Miura T, Ikeda Y, Matsuda E, Saito K, Miki T, et al. Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repair. Cardiovasc Pathol. 2005;14:241-6. DOI: 10.1016/j.carpath.2005.05.00410.1016/j.carpath.2005.05.004Open DOISearch in Google Scholar

45. Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxidants & redox signaling. 2013;18:1100-13. DOI: 10.1089/ars.2012.484910.1089/ars.2012.4849Open DOISearch in Google Scholar

46. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91:988-98. DOI: 10.1161/01. RES.0000043825.01705.1B10.1161/01.RES.0000043825.01705.1Open DOISearch in Google Scholar

47. Bozkurt B, Mann DL, Deswal A. Biomarkers of inflammation in heart failure. Heart Fail Rev. 2010;15:331-41. DOI: 10.1007/s10741-009-9140-3 10.1007/s10741-009-9140-3Open DOISearch in Google Scholar

48. Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR, Prabhu SD. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res. 2014;114:266-82.DOI: 10.1161/CIRCRESAHA.113.30172010.1161/CIRCRESAHA.113.301720Open DOISearch in Google Scholar

49. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;339:172-7. DOI: 10.1126/science. 123072110.1126/.1230721Open DOISearch in Google Scholar

50. Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell metab. 2014;19:821-35. DOI: 10.1016/j.cmet.2014.03.02910.1016/j.cmet.2014.03.029Open DOISearch in Google Scholar

51. Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36:1163-70. DOI: 10.1093/eurheartj/ehu50510.1093/eurheartj/ehu505Open DOISearch in Google Scholar

52. Nahrendorf M, Swirski FK. Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J. 2016;37:868-72. DOI: 10.1093/eurheartj/ehv45310.1093/eurheartj/ehv453Open DOISearch in Google Scholar

53. Seropian IM, Toldo S, Van Tassell BW, Abbate A. Anti- inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction. J Am Coll Cardiol. 2014;63:1593-603. DOI: 10.1016/j.jacc.2014.01.01410.1016/j.jacc.2014.01.014Open DOISearch in Google Scholar

54. Giugliano GR, Giugliano RP, Gibson CM, Kuntz RE. Meta-analysis of corticosteroid treatment in acute myocardial infarction. Am J Cardiol. 2003;91:1055-9. DOI: 10.1016/S0002-9149(03)00148-610.1016/S0002-9149(03)00148-6Open DOISearch in Google Scholar

55. Gibson CM, Pride YB, Aylward PE, Col JJ, Goodman SG, Gulba D, et al. Association of non-steroidal anti- inflammatory drugs with outcomes in patients with ST-segment elevation myocardial infarction treated with fibrinolytic therapy: an ExTRACT-TIMI 25 analysis. J Thromb Thrombolysis. 2009;27:11-7. DOI: 10.1007/s11239-008-0264-410.1007/s11239-008-0264-4Open DOISearch in Google Scholar

56. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569-619.Search in Google Scholar

57. Morton AC, Rothman AM, Greenwood JP, Gunn J, Chase A, Clarke B, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J. 2015;36:377-84. DOI: 10.1093/eurheartj/ehu27210.1093/eurheartj/ehu272Open DOISearch in Google Scholar

58. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin- 1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597-605. DOI: 10.1016/j.ahj.2011.06.01210.1016/j.ahj.2011.06.012Open DOISearch in Google Scholar

59. Swirski FK, Robbins CS. Neutrophils usher monocytes into sites of inflammation. Circ Res. 2013;112:744-5. DOI: 10.1161/CIRCRESAHA.113.30086710.1161/CIRCRESAHA.113.300867Open DOISearch in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo