Inflammation in acute coronary syndrome: Expression of TLR2 mRNA is increased in platelets of patients with ACS

English version

Autoři: Lukas Andreas Heger ^aff001; Marcus Hortmann ^aff001; Madlin Albrecht ^aff001; Christian Colberg ^aff001; Karlheinz Peter ^aff002; Thilo Witsch ^aff001; Daniela Stallmann ^aff001; Andreas Zirlik ^aff001; Christoph Bode ^aff001; Daniel Duerschmied ^aff001; Ingo Ahrens ^aff001
Působiště autorů: Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany ^aff001; Baker IDI Heart and Diabetes Institute, Melbourne, Australia ^aff002; Department of Cardiology, Medical University of Graz, Graz, Austria ^aff003; Department of Cardiology and Medical Intensive Care, Augustinerinnen Hospital, Academic Teaching Hospital University of Cologne, Cologne, Germany ^aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224181

Souhrn

Background

Platelets are key components in atherogenesis and determine the course of its clinical sequelae acute coronary syndrome (ACS). Components of the innate immune system—the superfamily of TLR receptors–are present in platelets and represent a link between atherothrombosis and inflammation. We hypothesize that alteration in platelet TLR mRNA expression is a result of inflammation driving coronary atherosclerosis and may represent an alternative platelet activation pathway in ACS.

TLR2-, TLR4- and TLR9- mRNA-expression was determined in ACS patients and compared to patients with invasive exclusion of atherosclerotic lesions of coronary arteries.

Methods

A total of fifty-four patients were enrolled in this clinical retrospective cohort single centre study. Total RNA from sepharose-filtered highly purified platelets was isolated using acid guanidinium thiocyanate-phenol-chloroform extraction and transcribed to cDNA using a first strand cDNA synthesis kit. To determine absolute copy numbers of TLR2, TLR4 and TLR9 we used plasmid based quantitative PCR with normalisation to an internal control.

Results

We found that mRNA expression levels of TLR2 but not TLR 4 and 9 are up-regulated in platelets of patients with ACS when compared to patients without coronary atherosclerosis.

Conclusion

Our results suggest elevated TLR2 mRNA expression in platelets as a biomarker reflecting the underlying inflammation in ACS and possibly severity of coronary atherosclerosis. Platelet TLR2 may represent a link between inflammation and atherothrombosis in ACS.

Klíčová slova:

Coronary heart disease – Immune response – Inflammation – Messenger RNA – Platelet activation – Platelet aggregation – Platelets – Toll-like receptors

Zdroje

1. Ruggeri ZM. Platelets in atherothrombosis. Nature Medicine. 2002;8:1227. doi: 10.1038/nm1102-1227 12411949

2. Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res. 2004;61(3):498–511. doi: 10.1016/j.cardiores.2003.11.036 14962480.

3. Lievens D, von Hundelshausen P. Platelets in atherosclerosis. Thromb Haemost. 2011;106(5):827–38. doi: 10.1160/TH11-08-0592 22012554.

4. van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol. 2009;85(2):195–204. doi: 10.1189/jlb.0708400 18948548.

5. Silvain J, Collet JP, Nagaswami C, Beygui F, Edmondson KE, Bellemain-Appaix A, et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol. 2011;57(12):1359–67. doi: 10.1016/j.jacc.2010.09.077 21414532; PubMed Central PMCID: PMC3071619.

6. Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol. 2001;154(3):485–90. doi: 10.1083/jcb.200105058 11489912; PubMed Central PMCID: PMC2196422.

7. Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood. 2010;116(20):4317–27. doi: 10.1182/blood-2010-01-261206 20705757; PubMed Central PMCID: PMC2993630.

8. Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol. 2005;83(2):196–8. doi: 10.1111/j.1440-1711.2005.01314.x 15748217.

9. Falati S, Patil S, Gross PL, Stapleton M, Merrill-Skoloff G, Barrett NE, et al. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood. 2006;107(2):535–41. doi: 10.1182/blood-2005-04-1512 PubMed Central PMCID: PMC1895610. 16166583

10. Schubert P, Devine DV. De novo protein synthesis in mature platelets: a consideration for transfusion medicine. Vox Sang. 2010;99(2):112–22. doi: 10.1111/j.1423-0410.2010.01333.x 20345520.

11. Sottile J, Mosher DF, Fullenweider J, George JN. Human platelets contain mRNA transcripts for platelet factor 4 and actin. Thromb Haemost. 1989;62(4):1100–2. 2617457.

12. Deutsch VR, Tomer A. Megakaryocyte development and platelet production. Br J Haematol. 2006;134(5):453–66. doi: 10.1111/j.1365-2141.2006.06215.x 16856888.

13. Avraham H, Price DJ. Regulation of megakaryocytopoiesis and platelet production by tyrosine kinases and tyrosine phosphatases. Methods. 1999;17(3):250–64. doi: 10.1006/meth.1998.0735 10080910.

14. Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest. 2005;115(12):3339–47. doi: 10.1172/JCI26674 16322778; PubMed Central PMCID: PMC1297257.

15. Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell. 2005;122(3):379–91. doi: 10.1016/j.cell.2005.06.015 16096058; PubMed Central PMCID: PMC4401993.

16. Schwertz H, Tolley ND, Foulks JM, Denis MM, Risenmay BW, Buerke M, et al. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med. 2006;203(11):2433–40. doi: 10.1084/jem.20061302 17060476; PubMed Central PMCID: PMC2118136.

17. Kieffer N, Guichard J, Farcet JP, Vainchenker W, Breton-Gorius J. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem. 1987;164(1):189–95. doi: 10.1111/j.1432-1033.1987.tb11010.x 3830180.

18. Weyrich AS, Lindemann S, Tolley ND, Kraiss LW, Dixon DA, Mahoney TM, et al. Change in protein phenotype without a nucleus: translational control in platelets. Semin Thromb Hemost. 2004;30(4):491–8. doi: 10.1055/s-2004-833484 15354270.

19. Eicher JD, Wakabayashi Y, Vitseva O, Esa N, Yang Y, Zhu J, et al. Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction. Platelets. 2016;27(3):230–9. doi: 10.3109/09537104.2015.1083543 26367242; PubMed Central PMCID: PMC4933502.

20. Rondina MT, Schwertz H, Harris ES, Kraemer BF, Campbell RA, Mackman N, et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost. 2011;9(4):748–58. doi: 10.1111/j.1538-7836.2011.04208.x 21255247; PubMed Central PMCID: PMC3071458.

21. Shashkin PN, Brown GT, Ghosh A, Marathe GK, McIntyre TM. Lipopolysaccharide is a direct agonist for platelet RNA splicing. J Immunol. 2008;181(5):3495–502. doi: 10.4049/jimmunol.181.5.3495 18714022; PubMed Central PMCID: PMC2551315.

22. Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, et al. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res. 2009;104(3):346–54. doi: 10.1161/CIRCRESAHA.108.185785 19106411; PubMed Central PMCID: PMC2732983.

23. Rivadeneyra L, Carestia A, Etulain J, Pozner RG, Fondevila C, Negrotto S, et al. Regulation of platelet responses triggered by Toll-like receptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. Thromb Res. 2014;133(2):235–43. doi: 10.1016/j.thromres.2013.11.028 24331207.

24. Chandran S, Watkins J, Abdul-Aziz A, Shafat M, Calvert PA, Bowles KM, et al. Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST-Segment Elevation Myocardial Infarction. J Am Heart Assoc. 2017;6(5). doi: 10.1161/JAHA.117.005868 28468787; PubMed Central PMCID: PMC5524113.

25. Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res. 2014;114(12):1867–79. doi: 10.1161/CIRCRESAHA.114.302699 24902971; PubMed Central PMCID: PMC4078767.

26. Campbell IC, Suever JD, Timmins LH, Veneziani A, Vito RP, Virmani R, et al. Biomechanics and inflammation in atherosclerotic plaque erosion and plaque rupture: implications for cardiovascular events in women. PLoS One. 2014;9(11):e111785. doi: 10.1371/journal.pone.0111785 25365517; PubMed Central PMCID: PMC4218818.

27. Semple JW, Italiano JE Jr., Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–74. doi: 10.1038/nri2956 21436837.

28. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20. doi: 10.1016/j.cell.2010.01.022 20303872

29. Shiraki R, Inoue N, Kawasaki S, Takei A, Kadotani M, Ohnishi Y, et al. Expression of Toll-like receptors on human platelets. Thromb Res. 2004;113(6):379–85. doi: 10.1016/j.thromres.2004.03.023 15226092.

30. Koupenova M, Mick E, Mikhalev E, Benjamin EJ, Tanriverdi K, Freedman JE. Sex differences in platelet toll-like receptors and their association with cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2015;35(4):1030–7. doi: 10.1161/ATVBAHA.114.304954 25657311; PubMed Central PMCID: PMC4376646.

31. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–50. doi: 10.1016/j.immuni.2011.05.006 21616434.

32. Ward JR, Bingle L, Judge HM, Brown SB, Storey RF, Whyte MK, et al. Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb Haemost. 2005;94(4):831–8. 16270639.

33. Aslam R, Speck ER, Kim M, Crow AR, Bang KW, Nestel FP, et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood. 2006;107(2):637–41. doi: 10.1182/blood-2005-06-2202 16179373.

34. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394–7. doi: 10.1038/41131 9237759.

35. Li S, Strelow A, Fontana EJ, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A. 2002;99(8):5567–72. doi: 10.1073/pnas.082100399 11960013; PubMed Central PMCID: PMC122810.

36. Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation. 2002;105(10):1158–61. 11889007.

37. Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation. 2005;111(20):2654–61. doi: 10.1161/CIRCULATIONAHA.104.498865 15883205.

38. Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM. Toll-like receptors in ischemia-reperfusion injury. Shock. 2009;32(1):4–16. doi: 10.1097/SHK.0b013e318193e333 19008778.

39. Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ, et al. Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation. 2006;114(1 Suppl):I270–4. doi: 10.1161/CIRCULATIONAHA.105.000901 16820585.

40. Cognasse F, Garraud O. Human platelets exhibit infectious-pathogen-binding ligands and participate to inflammation (and more?). Exp Hematol. 2005;33(10):1081–2. doi: 10.1016/j.exphem.2005.06.033 16219529.

41. Berthet J, Damien P, Hamzeh-Cognasse H, Pozzetto B, Garraud O, Cognasse F. Toll-like receptor 4 signal transduction in platelets: novel pathways. Br J Haematol. 2010;151(1):89–92. doi: 10.1111/j.1365-2141.2010.08292.x 20618335.

42. Mukherjee S, Karmakar S, Babu SP. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis. 2016;20(2):193–204. doi: 10.1016/j.bjid.2015.10.011 26775799.

43. Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952–61. doi: 10.1182/blood-2011-03-343061 21673343; PubMed Central PMCID: PMC3158722.

44. Vallance TM, Zeuner MT, Williams HF, Widera D, Vaiyapuri S. Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis. Mediators Inflamm. 2017;2017:9605894. doi: 10.1155/2017/9605894 29170605; PubMed Central PMCID: PMC5664350.

45. Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest. 2005;115(11):3149–56. doi: 10.1172/JCI25482 16211093; PubMed Central PMCID: PMC1242192.

46. Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004;101(29):10679–84. doi: 10.1073/pnas.0403249101 15249654; PubMed Central PMCID: PMC489994.

47. Roy A, Srivastava M, Saqib U, Liu D, Faisal SM, Sugathan S, et al. Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways. Int Immunopharmacol. 2016;40:79–89. doi: 10.1016/j.intimp.2016.08.026 27584057.

48. Carl VS, Brown-Steinke K, Nicklin MJ, Smith MF Jr. Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages. J Biol Chem. 2002;277(20):17448–56. doi: 10.1074/jbc.M111847200 11877429.

49. Re F, Strominger JL. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem. 2001;276(40):37692–9. doi: 10.1074/jbc.M105927200 11477091.

50. LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M, et al. Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol. 2003;171(12):6680–9. doi: 10.4049/jimmunol.171.12.6680 14662871.

51. Henrick BM, Yao XD, Taha AY, German JB, Rosenthal KL. Insights into Soluble Toll-Like Receptor 2 as a Downregulator of Virally Induced Inflammation. Front Immunol. 2016;7:291. doi: 10.3389/fimmu.2016.00291 27531999; PubMed Central PMCID: PMC4969314.

52. Ueland T, Espevik T, Kjekshus J, Gullestad L, Omland T, Squire IB, et al. Mannose binding lectin and soluble Toll-like receptor 2 in heart failure following acute myocardial infarction. J Card Fail. 2006;12(8):659–63. doi: 10.1016/j.cardfail.2006.07.002 17045187.

53. Panigrahi S, Ma Y, Hong L, Gao D, West XZ, Salomon RG, et al. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res. 2013;112(1):103–12. doi: 10.1161/CIRCRESAHA.112.274241 23071157; PubMed Central PMCID: PMC3537845.

54. Thon JN, Peters CG, Machlus KR, Aslam R, Rowley J, Macleod H, et al. T granules in human platelets function in TLR9 organization and signaling. J Cell Biol. 2012;198(4):561–74. doi: 10.1083/jcb.201111136 22908309; PubMed Central PMCID: PMC3514030.

55. Xie L, He S, Kong N, Zhu Y, Tang Y, Li J, et al. Cpg-ODN, a TLR9 Agonist, Aggravates Myocardial Ischemia/Reperfusion Injury by Activation of TLR9-P38 MAPK Signaling. Cell Physiol Biochem. 2018;47(4):1389–98. doi: 10.1159/000490828 29929196.

56. Omiya S, Omori Y, Taneike M, Protti A, Yamaguchi O, Akira S, et al. Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation. Am J Physiol Heart Circ Physiol. 2016;311(6):H1485–H97. doi: 10.1152/ajpheart.00481.2016 27769998; PubMed Central PMCID: PMC5206340.

57. Raby AC, Le Bouder E, Colmont C, Davies J, Richards P, Coles B, et al. Soluble TLR2 reduces inflammation without compromising bacterial clearance by disrupting TLR2 triggering. J Immunol. 2009;183(1):506–17. doi: 10.4049/jimmunol.0802909 19542461.

58. Napolitano LM. Sepsis 2018: Definitions and Guideline Changes. Surg Infect (Larchmt). 2018;19(2):117–25. doi: 10.1089/sur.2017.278 29447109.

59. Wasserman AM. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011;84(11):1245–52. 22150658.

60. Lutgens E, van Suylen RJ, Faber BC, Gijbels MJ, Eurlings PM, Bijnens AP, et al. Atherosclerotic plaque rupture: local or systemic process? Arterioscler Thromb Vasc Biol. 2003;23(12):2123–30. doi: 10.1161/01.ATV.0000097783.01596.E2 14512372.

61. Spirig R, Tsui J, Shaw S. The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease. Cardiol Res Pract. 2012;2012:181394. doi: 10.1155/2012/181394 22577589; PubMed Central PMCID: PMC3346970.

62. Rowley JW, Oler AJ, Tolley ND, Hunter BN, Low EN, Nix DA, et al. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood. 2011;118(14):e101–11. doi: 10.1182/blood-2011-03-339705 21596849; PubMed Central PMCID: PMC3193274.

63. Wyss CA, Neidhart M, Altwegg L, Spanaus KS, Yonekawa K, Wischnewsky MB, et al. Cellular actors, Toll-like receptors, and local cytokine profile in acute coronary syndromes. Eur Heart J. 2010;31(12):1457–69. doi: 10.1093/eurheartj/ehq084 20447947.

64. Gurses KM, Kocyigit D, Yalcin MU, Canpinar H, Oto MA, Ozer N, et al. Enhanced Platelet Toll-like Receptor 2 and 4 Expression in Acute Coronary Syndrome and Stable Angina Pectoris. Am J Cardiol. 2015;116(11):1666–71. doi: 10.1016/j.amjcard.2015.08.048 26455385.

65. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky S. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst J. 2007;34(1):11–8. 17420787; PubMed Central PMCID: PMC1847934.

66. Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, et al. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med. 2018;378(4):345–53. doi: 10.1056/NEJMoa1702090 29365305.

67. Cohen JA, Leeksma CH. Determination of the life span of human blood platelets using labelled diisopropylfluorophosphonate. J Clin Invest. 1956;35(9):964–9. doi: 10.1172/JCI103356 13367192; PubMed Central PMCID: PMC441670.

68. Al Shahi H, Shimada K, Miyauchi K, Yoshihara T, Sai E, Shiozawa T, et al. Elevated Circulating Levels of Inflammatory Markers in Patients with Acute Coronary Syndrome. Int J Vasc Med. 2015;2015:805375. doi: 10.1155/2015/805375 26504600; PubMed Central PMCID: PMC4609512.

69. Beaulieu LM, Lin E, Morin KM, Tanriverdi K, Freedman JE. Regulatory effects of TLR2 on megakaryocytic cell function. Blood. 2011;117(22):5963–74. doi: 10.1182/blood-2010-09-304949 21454454; PubMed Central PMCID: PMC3112041.

70. Ghasiyari H, Rostami-Nejad M, Amani D, Rostami K, Pourhoseingholi MA, Asadzadeh-Aghdaei H, et al. Diverse Profiles of Toll-Like Receptors 2, 4, 7, and 9 mRNA in Peripheral Blood and Biopsy Specimens of Patients with Celiac Disease. J Immunol Res. 2018;2018:7587095. doi: 10.1155/2018/7587095 30057921; PubMed Central PMCID: PMC6051003.

71. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999;11(4):443–51. doi: 10.1016/s1074-7613(00)80119-3 10549626.

72. Hally KE, La Flamme AC, Larsen PD, Harding SA. Toll-like receptor 9 expression and activation in acute coronary syndrome patients on dual anti-platelet therapy. Thromb Res. 2016;148:89–95. doi: 10.1016/j.thromres.2016.10.026 27815972.

Inflammation in acute coronary syndrome: Expression of TLR2 mRNA is increased in platelets of patients with ACS

Souhrn

Background

Methods

Results

Conclusion

Klíčová slova:

Zdroje

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