Immune-mediated mechanisms of atherosclerosis and implications for the clinic

Expert Review of Clinical Immunology

Volumn 12, Issue 11, 2016, Pages 1217-1237

  Nus, Meritxell ^a   Mallat, Ziad ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

adaptive immune response; anti inflammatory therapies; atherosclerosis; Innate immune response

Indexed keywords

CD4 ANTIGEN; INTERLEUKIN 1; INTERLEUKIN 6; METHOTREXATE; PHOSPHOLIPASE A2; SECRETORY PHOSPHOLIPASE A2;

ADAPTIVE IMMUNITY; ATHEROSCLEROSIS; CARDIOVASCULAR RISK; CD4+ T LYMPHOCYTE; CONTROLLED CLINICAL TRIAL (TOPIC); HUMAN; IMMUNOMODULATION; IMMUNOPATHOGENESIS; INFLAMMATION; INNATE IMMUNITY; MULTICENTER STUDY (TOPIC); NONHUMAN; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; TH17 CELL; TH2 CELL; IMMUNOLOGY; MOLECULARLY TARGETED THERAPY;

ADAPTIVE IMMUNITY; ATHEROSCLEROSIS; HUMANS; IMMUNITY, INNATE; INFLAMMATION; MOLECULAR TARGETED THERAPY;

EID: 84992079507     PISSN: 1744666X     EISSN: 17448409     Source Type: Journal    
DOI: 10.1080/1744666X.2016.1195686     Document Type: Review

References (200)

1. A.Weber, P.Wasiliew, M.Kracht Interleukin-1 (IL-1) pathway. Sci Signal [Internet]. 2010;3(105):cm1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20086235
2. Y.Kobayashi, K.Yamamoto, T.Saido, et al. Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci U S A [Internet]. 1990;87(14):5548–5552. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=54362&tool=pmcentrez&rendertype=abstract
3. Y.Zheng, M.Humphry, J.J.Maguire, et al. Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1α, controlling necrosis-induced sterile inflammation. Immunity. 2013;38(2):285–295.
4. S.Freigang, F.Ampenberger, A.Weiss, et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat Immunol [Internet]. 2013;14(10):1045–1053. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23995233
5. J.-S.Moon, S.Lee, M.-A.Park, et al. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest [Internet]. 2015;125(2):665–680. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4319445&tool=pmcentrez&rendertype=abstract
6. C.Gabay, C.Lamacchia, G.Palmer. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol [Internet]. 2010;6(4):232–241. Available from: http://www.nature.com/doifinder/10.1038/nrrheum.2010.4
7. P.Duewell, H.Kono, K.J.Rayner, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature [Internet]. 2010;464(7293):1357–1361. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2946640&tool=pmcentrez&rendertype=abstract
8. F.J.Sheedy, A.Grebe, K.J.Rayner, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol [Internet]. 2013;14(8):812–820. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3720827&tool=pmcentrez&rendertype=abstract
9. R.Elhage, A.Maret, M.-T.Pieraggi, et al. Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E deficient mice. Circulation [Internet]. 1998;97(3):242–244. Available from: http://circ.ahajournals.org.ezp-prod1.hul.harvard.edu/content/97/3/242.long
10. C.M.Devlin, G.Kuriakose, E.Hirsch, et al. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A. 2002;99(9):6280–6285.
11. F.Merhi-Soussi, B.R.Kwak, D.Magne, et al. Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice. Cardiovasc Res. 2005;66(3):583–593.
12. M.R.Alexander, C.W.Moehle, J.L.Johnson, et al. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest. 2012;122(1):70–79.
13. K.Isoda, S.Sawada, N.Ishigami, et al. Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2004;24(6):1068–1073.
14. Y.Kamari, R.Werman-Venkert, A.Shaish, et al. Differential role and tissue specificity of interleukin-1α gene expression in atherogenesis and lipid metabolism. Atherosclerosis [Internet]. 2007;195(1):31–38. Available from: http://www.sciencedirect.com/science/article/pii/S0021915006007003
15. V.Bhaskar, J.Yin, A.M.Mirza, et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in apolipoprotein E-deficient mice. Atherosclerosis [Internet]. 2011;216(2):313–320. doi:10.1016/j.atherosclerosis.2011.02.026.
16. P.Libby, D.J.Wyler, M.W.Janicka, et al. Differential effects of human interleukin-1 on growth of human fibroblasts and vascular smooth muscle cells. Arteriosclerosis [Internet]. 1985;5(2):186–191. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3872118
17. M.P.Bevilacqua, J.S.Pober, M.E.Wheeler, et al. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest [Internet]. 1985;76(5):2003–2011. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=424265&tool=pmcentrez&rendertype=abstract
18. R.Montesano. Leukocyte interleukins induce cultured endothelial cells to produce a highly organized, glycosaminoglycan-rich pericellular matrix. J Cell Biol [Internet]. 1984;99(5):1706–1715. Available from: http://jcb.rupress.org/cgi/content/long/99/5/1706
19. S.Martin, K.Maruta, V.Burkart, et al. IL-1 and IFN-gamma increase vascular permeability. Immunology. 1988;64(Feb):301–305.
20. A.M.Wang, M.V.Doyle, D.F.Mark. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989;86(24):9717–9721.
21. J.Galea, J.Armstrong, P.Gadsdon, et al. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 1996;16(8):1000–1006.
22. M.C.H.Clarke, S.Talib, N.L.Figg, et al. Vascular smooth muscle cell apoptosis induces interleukin-1-directed inflammation:effects of hyperlipidemia-mediated inhibition of phagocytosis. Circ Res. 2010;106(2):363–372.
23. B.W.Van Tassell, J.M.V.Raleigh, A.Abbate. Targeting interleukin-1 in heart failure and inflammatory heart disease. Curr Heart Fail Rep. 2015;12(1):33–41.
24. I.Ikonomidis, J.Lekakis, I.Revela, et al. Increased circulating C-reactive protein and macrophage-colony stimulating factor are complementary predictors of long-term outcome in patients with chronic coronary artery disease. Eur Heart J. 2005;26(16):1618–1624.
25. T.Saitoh, H.Kishida, Y.Tsukada, et al. Clinical significance of increased plasma concentration of macrophage colony-stimulating factor in patients with angina pectoris. J Am Coll Cardiol [Internet]. 2000;35(3):655–665. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0735109799005835
26. T.Kilic, D.Ural, E.Ural, et al. Relation between proinflammatory to anti-inflammatory cytokine ratios and long-term prognosis in patients with non-ST elevation acute coronary syndrome. Heart [Internet]. 2006;92(8):1041–1046. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1861097&tool=pmcentrez&rendertype=abstract
27. L.C.Correia, G.Garcia, F.Kalil, et al. Prognostic value of TIMI score versus GRACE score in ST-segment elevation myocardial infarction. Arq Bras Cardiol [Internet]. 2014;103(2):98–106. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25029471
28. S.Tsimikas, G.W.Duff, P.B.Berger, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol. 2014;63(17):1724–1734.
29. J.K.Tarlow, A.I.Blakemore, A.Lennard, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet [Internet]. 1993;91(4):403–404. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8500797
30. P.S.Olofsson, Y.Sheikine, K.Jatta, et al. A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development. The interleukin-1beta:interleukin-1receptor antagonist balance in atherosclerosis. Circ J [Internet]. 2009;73(8):1531–1536. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19574724
31. S.E.Francis, N.J.Camp, R.M.Dewberry, et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation. 1999;99(7):861–866.
32. B.Vohnout, A.Di Castelnuovo, R.Trotta, et al. Interleukin-1 gene cluster polymorphisms and risk of coronary artery disease. Haematologica [Internet]. 2003;88(1):54–60. Available from: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L36168855\nhttp://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=03906078&id=doi:&atitle=Interleukin-1+gene+cluster+polymorphisms+and+risk+of+coronary+artery+disease&stitle=Haematologica&
33. D.Freitag, A.S.Butterworth, P.Willeit, et al. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist:a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2015;3(4):243–253.
34. C.A.Dinarello, A.Simon, J.W.M.Van Der Meer. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov [Internet]. 2012;11(8):633–652. Available from: http://www.nature.com/doifinder/10.1038/nrd3800
35. A.C.Morton, A.M.K.Rothman, J.P.Greenwood, 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 [Internet]. 2014:377–384. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25079365
36. P.M.Ridker. Closing the loop on inflammation and atherothrombosis:why perform the CIRT and CANTOS trials? Trans Am Clin Climatol Assoc [Internet]. 2013;124:174–190. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3715939&tool=pmcentrez&rendertype=abstract
37. P.M.Ridker, C.P.Howard, V.Walter, et al. Effects of interleukin-1 inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126(23):2739–2748.• CANTOS is the largest clinical trial currently ongoing testing the anti-inflammatory theory of atherosclerosis, and more particularly the efficacy of IL1β blockade on clinical cardiovascular outcome in patients with coronary artery disease. A phase IIb showed that canakinumab significantly reduces inflammation without major effect on LDL- or HDL-cholesterol.
38. E.Ben-Chetrit, M.Levy. Colchicine:1998 update. Semin Arthritis Rheum. 1998;28(1):48–59.
39. N.C.Raju, Q.Yi, M.Nidorf, et al. Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary syndrome or acute stroke:a pilot randomized controlled trial. J Thromb Thrombolysis. 2012;33(1):88–94.
40. G.J.Martínez, S.Robertson, J.Barraclough, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc [Internet]. 2015;4(8):e002128. Available from: http://jaha.ahajournals.org/lookup/doi/10.1161/JAHA.115.002128
41. S.M.Nidorf, J.W.Eikelboom, C.A.Budgeon, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol [Internet]. 2013;61(4):404–410. doi:10.1016/j.jacc.2012.10.027.
42. S.Verma, J.W.Eikelboom, S.M.Nidorf, et al. Colchicine in cardiac disease:a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord [Internet]. 2015;15:96. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4553011&tool=pmcentrez&rendertype=abstract
43. B.N.Cronstein. Low-dose methotrexate:a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev [Internet]. 2005;57(2):163–172. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15914465
44. L.Genestier, R.Paillot, S.Fournel, et al. Immunosuppressive properties of methotrexate:apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998;102(2):322–328.
45. Z.Ortiz, B.Shea, M.E.Suarez-Almazor, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol. 1998;25(1):36–43.
46. G.Nesher, T.G.Osborn, T.L.Moore. Effect of treatment with methotrexate, hydroxychloroquine, and prednisone on lymphocyte polyamine levels in rheumatoid arthritis:correlation with the clinical response and rheumatoid factor synthesis. Clin Exp Rheumatol. 1997;15(4):343–347.
47. M.C.Montesinos, M.Takedachi, L.F.Thompson, et al. The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5’-nucleotidase:findings in a study of ecto-5’-nucleotidase gene-deficient mice. Arthritis Rheum. 2007;56(5):1440–1445.
48. C.Roubille, V.Richer, T.Starnino, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis:a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(3):480–489.
49. A.Bulgarelli, A.A.Martins Dias, B.Caramelli, et al. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol [Internet]. 2012;59(4):308–314. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22113347
50. C.C.Thornton, F.Al-Rashed, D.Calay, et al. Methotrexate-mediated activation of an AMPK-CREB-dependent pathway:a novel mechanism for vascular protection in chronic systemic inflammation. Ann Rheum Dis [Internet]. 2015:1–10. Available from: http://ard.bmj.com/cgi/doi/10.1136/annrheumdis-2014-206305
51. E.Coomes, E.S.L.Chan, A.B.Reiss. Methotrexate in atherogenesis and cholesterol metabolism. Cholesterol [Internet]. 2011;2011:503028. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3070167&tool=pmcentrez&rendertype=abstract
52. A.B.Reiss, B.N.Cronstein. Regulation of foam cells by adenosine. Arterioscler Thromb Vasc Biol. 2012;32(4):879–886.
53. R.Micha, F.Imamura, M.Wyler Von Ballmoos, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108:1362–1370.
54. H.K.Choi, M.A.Hernán, J.D.Seeger, et al. Methotrexate and mortality in patients with rheumatoid arthritis:a prospective study. Lancet [Internet]. 2002;359(9313):1173–1177. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11955534
55. J.Franklin, T.M.Farragher, M.Lunt, et al. Excess risk of hospital admission for cardiovascular disease within the first 7 years from onset of inflammatory polyarthritis. Ann Rheum Dis [Internet]. 2010;69(9):1660–1664. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20498206
56. S.L.Westlake, A.N.Colebatch, J.Baird, et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis:a systematic literature review. Rheumatology. 2010;49(2):295–307.
57. M.C.Hochberg, S.S.Johnston, A.K.John. The incidence and prevalence of extra-articular and systemic manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis between 1999 and 2006. Curr Med Res Opin [Internet]. 2008;24(2):469–480. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18179735
58. S.Prodanovich, S.Prodanowich, F.Ma, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52(2):262–267.
59. B.M.Everett, A.D.Pradhan, D.H.Solomon, et al. Rationale and design of the cardiovascular inflammation reduction trial:a test of the inflammatory hypothesis of atherothrombosis. Am Heart J [Internet]. 2013;166(2):199–207.e15. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3888829&tool=pmcentrez&rendertype=abstract
60. J.Scheller, A.Chalaris, D.Schmidt-Arras, et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta Mol Cell Res. 2011;1813(5):878–888.
61. T.Kishimoto. IL-6:from its discovery to clinical applications. Int Immunol. 2010;22(5):347–352.
62. P.C.Heinrich, J.V.Castell, T.Andus. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621–636.
63. B.A.Croker, D.L.Krebs, J.-G.Zhang, et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol. 2003;4(6):540–545.
64. H.Yasukawa, M.Ohishi, H.Mori, et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol. 2003;4(6):551–556.
65. J.Mauer, B.Chaurasia, J.Goldau, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol [Internet]. 2014;15(5):423–430. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24681566
66. S.Rose-John. Il-6 trans-signaling via the soluble IL-6 receptor:importance for the proinflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237–1247.
67. S.A.Jones, J.Scheller, S.Rose-John. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375–3383.
68. M.Diamant, K.Rieneck, N.Mechti, et al. Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin-6 signal transducer gp130. FEBS Lett. 1997;412(2):379–384.
69. G.W.Jones, R.M.McLoughlin, V.J.Hammond, et al. Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J Immunol [Internet]. 2010;184:2130–2139. doi:10.4049/jimmunol.0901528.
70. S.Keidar, R.Heinrich, M.Kaplan, et al. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDL:a possible role for interleukin-6. Arterioscler Thromb Vasc Biol [Internet]. 2001;21(9):1464–1469. Available from: http://atvb.ahajournals.org/content/21/9/1464.long
71. S.A.Huber, P.Sakkinen, D.Conze, et al. Interleukin-6 exacerbates early atherosclerosis in mice. Arter Thromb Vasc Biol [Internet]. 1999;19:2364–2367. Available from: http://atvb.ahajournals.org/content/19/10/2364\nhttp://atvb.ahajournals.org//subscriptions/\nhttp://atvb.ahajournals.org/
72. R.Elhage, S.Clamens, S.Besnard, et al. Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17β-estradiol in apolipoprotein E-deficient mice. Atherosclerosis [Internet]. 2001;156(2):315–320. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11395027
73. B.J.Van Lenten, A.C.Wagner, M.Navab, et al. Oxidized phospholipids induce changes in hepatic paraoxonase and apoJ but not monocyte chemoattractant protein-1 via interleukin-6. J Biol Chem. 2001;276(3):1923–1929.
74. L.Song, C.Schindler. IL-6 and the acute phase response in murine atherosclerosis. Atherosclerosis. 2004;177(1):43–51.
75. G.W.Jones, L.McLeod, C.L.Kennedy, et al. Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis. Atherosclerosis. 2015;238(2):321–328.
76. H.Schuett, R.Oestreich, G.H.Waetzig, et al. Trans-signaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012;32(2):281–290.
77. P.M.Ridker, N.Rifai, M.J.Stampfer, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation [Internet]. 2000;101(15):1767–1772. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10769275
78. E.Lindmark, E.Diderholm, L.Wallentin, et al. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease:effects of an early invasive or noninvasive strategy. JAMA [Internet]. 2001;286(17):2107–2113. Available from: http://jama.ama-assn.org/cgi/doi/10.1001/jama.286.17.2107\nhttp://www.ncbi.nlm.nih.gov/pubmed/11694151
79. G.Luc, J.M.Bard, I.Juhan-Vague, et al. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease:the PRIME study. Arterioscler Thromb Vasc Biol. 2003;23(7):1255–1261.
80. Z.-X.Fan, Q.Hua, Y.-P.Li, et al. Interleukin-6, but not soluble adhesion molecules, predicts a subsequent mortality from cardiovascular disease in patients with acute ST-segment elevation myocardial infarction. Cell Biochem Biophys. 2011;61(2):443–448.
81. N.Sarwar, A.S.Butterworth. Interleukin-6 receptor pathways in coronary heart disease:a collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205–1213.
82. A.D.Hingorani, J.P.Casas. The interleukin-6 receptor as a target for prevention of coronary heart disease:a mendelian randomisation analysis. Lancet [Internet]. 2012;379(9822):1214–1224. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3316968&tool=pmcentrez&rendertype=abstract\nhttp://www.sciencedirect.com/science/article/pii/S014067361260110X.• References [81] and [82] highlight the importance of performing large Mendelian randomization trials to identify causal variants/genes involved in cardiovascular diseases. It should be acknowledged, however, that those studies do not tell much about the differential roles of membrane versus trans IL6 signaling.
83. R.C.Ferreira, D.F.Freitag, A.J.Cutler, Functional IL6R 358Ala Allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013;9(4):e1003444.
84. M.A.R.Ferreira, M.C.Matheson, D.L.Duffy, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet. 2011;378(9795):1006–1014.
85. M.Luchtefeld, H.Schunkert, M.Stoll, et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med [Internet]. 2007;204(8):1935–1944. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2118681&tool=pmcentrez&rendertype=abstract
86. G.Jones. The AMBITION trial:tocilizumab monotherapy for rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6:189–195.
87. P.Emery, E.Keystone, H.P.Tony, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals:results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis [Internet]. 2008;67(11):1516–1523. Available from: http://ard.bmj.com/content/67/11/1516.long
88. C.Gabay, P.Emery, R.Van Vollenhoven, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA):a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541–1550.
89. I.B.McInnes, L.Thompson, J.T.Giles, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis:MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis [Internet]. 2013:1–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24368514
90. M.H.Schiff, J.M.Kremer, A.Jahreis, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther [Internet]. 2011;13(5):R141. Available from: http://arthritis-research.com/content/13/5/R141
91. Z.Mallat, G.Lambeau, A.Tedgui. Lipoprotein-associated and secreted phospholipases A2 in cardiovascular disease:roles as biological effectors and biomarkers. Circulation. 2010;122(21):2183–2200.
92. G.Theilmeier, B.De Geest, P.P.Van Veldhoven, et al. HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice. FASEB J [Internet]. 2000;14(13):2032–2039. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11023987
93. M.O.Hiltunen, M.Laitinen, M.P.Turunen, et al. Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta. Circulation. 2000;102(18):2262–2268.
94. D.De Keyzer, S.-A.Karabina, W.Wei, et al. Increased PAFAH and oxidized lipids are associated with inflammation and atherosclerosis in hypercholesterolemic pigs. Arterioscler Thromb Vasc Biol. 2009;29(12):2041–2046.
95. R.L.Wilensky, Y.Shi, E.R.Mohler, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008;14(10):1059–1066.
96. F.D.Kolodgie, A.P.Burke, K.S.Skorija, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26(11):2523–2529.
97. Emerging Risk Factors Collaboration, S.Erqou, S.Kaptoge, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA [Internet]. 2009;302(4):412–423. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19622820
98. P.L.A.S.C.Lp, A.Thompson, P.Gao, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality:collaborative analysis of 32 prospective studies. Lancet [Internet]. 2010;375:1536–1544. ST – Lipoprotein–associated phospholipase. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=20435228
99. Q.Wang, Y.Hao, X.Mo, et al. PLA2G7 gene polymorphisms and coronary heart disease risk:a meta-analysis. Thromb Res. 2010;126(6):498–503.
100. L.M.Polfus, R.A.Gibbs, E.Boerwinkle. Coronary heart disease and genetic variants with low phospholipase A2 activity. N Engl J Med. 2015;372(3):295–296.
101. E.R.Mohler, C.M.Ballantyne, M.H.Davidson, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent:the results of a multicenter, randomized, double-bl. J Am Coll Cardiol [Internet]. 2008;51(17):1632–1641. Available from: http://www.sciencedirect.com/science/article/pii/S073510970800569X
102. P.W.Serruys, H.M.Garcia-Garcia, P.Buszman, et al. Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118(11):1172–1182.
103. H.D.White. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med [Internet]. 2014:140330050005008. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24678955.
104. M.L.O’Donoghue, E.Braunwald, H.D.White, et al. Effect of darapladib on major coronary events after an acute coronary syndrome:the SOLID-TIMI 52 randomized clinical trial. JAMA [Internet].2014;312(10):1006–1015. Available from: http://jama.jamanetwork.com/article.aspx?articleid=1900827.•• References [103] and [104] demonstrate the futility of Lp-PLA2 inhibition in the setting of coronary artery disease.
105. H.Niessen. Type II secretory phospholipase A2 in cardiovascular disease:a mediator in atherosclerosis and ischemic damage to cardiomyocytes? Cardiovasc Res [Internet]. 2003;60(1):68–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14522408
106. U.J.F.Tietge, C.Maugeais, W.Cain, et al. Overexpression of secretory phospholipase A2 causes rapid catabolism and altered tissue uptake of high density lipoprotein cholesteryl ester and apolipoprotein A-I. J Biol Chem. 2000;275(14):10077–10084.
107. N.R.Webb, M.A.Bostrom, S.J.Szilvassy, et al. Macrophage-expressed group IIA secretory phospholipase A2 increases atherosclerotic lesion formation in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23(2):263–268.
108. M.A.Bostrom, B.B.Boyanovsky, C.T.Jordan, et al. Group V secretory phospholipase A2 promotes atherosclerosis:evidence from genetically altered mice. Arterioscler Thromb Vasc Biol. 2007;27(3):600–606.
109. H.Ait-Oufella, O.Herbin, C.Lahoute, et al. Group X secreted phospholipase a2 limits the development of atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol. 2013;33(3):466–473.
110. H.Fraser, C.Hislop, R.M.Christie, et al. Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice. J Cardiovasc Pharmacol [Internet]. 2009;53(1):60–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19129734
111. Z.Shaposhnik, X.Wang, J.Trias, et al. The synergistic inhibition of atherogenesis in apoE-/- mice between pravastatin and the sPLA2 inhibitor varespladib (A-002). J Lipid Res [Internet]. 2009;50(4):623–629. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2656655&tool=pmcentrez&rendertype=abstract
112. K.Kugiyama, Y.Ota, K.Takazoe, et al. Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease. Circulation. 1999;100(12):1280–1284.
113. P.-Y.Liu, Y.-H.Li, W.-C.Tsai, et al. Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary intervention. Eur Heart J. 2003;24(20):1824–1832.
114. W.Koenig, D.Twardella, H.Brenner, et al. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol. 2006;26(7):1586–1593.
115. M.S.Sabatine, D.A.Morrow, M.O’Donoghue, et al. Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;27(11):2463–2469.
116. M.V.Holmes, H.J.Exeter, L.Folkersen, et al. Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease:modified Mendelian randomization analysis using PLA2G5 expression levels. Circ Cardiovasc Genet [Internet]. 2014;7(2):144–150. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4212409&tool=pmcentrez&rendertype=abstract
117. M.Guardiola, H.J.Exeter, C.Perret, et al. PLA2G10 gene variants, sPLA2 activity, and coronary heart disease risk. Circ Cardiovasc Genet. 2015;8(2):356–362.
118. R.S.Rosenson, C.Hislop, D.McConnell, et al. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study):a phase II double-blind, randomised, placebo-controlled trial. Lancet. 2009;373(9664):649–658.
119. R.S.Rosenson, M.Elliott, Y.Stasiv, et al. Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease. Eur Heart J. 2011;32(8):999–1005.
120. R.S.Rosenson, C.Hislop, M.Elliott, et al. Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. J Am Coll Cardiol. 2010;56(14):1079–1088.
121. S.J.Nicholls, J.J.P.Kastelein, G.G.Schwartz, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome:the VISTA-16 randomized clinical trial. JAMA [Internet].2014;311(3):252–262. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24247616.• This paper demonstrates the futility of sPLA2 inhibition in patients with acute coronary syndromes. Concomitant Mendelian randomization studies could not support a causal role for sPLA2 type IIA in coronary artery disease (see Refs. [116] and [117]).
122. K.Tse, H.Tse, J.Sidney, et al. T cells in atherosclerosis. Int Immunol [Internet]. 2013;25(11):615–622. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24154816\nhttp://intimm.oxfordjournals.org/content/25/11/615.full.pdf
123. Z.Mallat, S.Taleb, H.Ait-Oufella, et al. The role of adaptive T cell immunity in atherosclerosis. J Lipid Res [Internet]. 2009;50(Suppl):S364–S369. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19050311
124. S.Morris-Rosenfeld, M.J.Lipinski, C.A.McNamara. Understanding the role of B cells in atherosclerosis:potential clinical implications. Expert Rev Clin Immunol [Internet]. 2014;10(1):77–89. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4358742&tool=pmcentrez&rendertype=abstract
125. S.Taleb, A.Tedgui, Z.Mallat. IL-17 and Th17 cells in atherosclerosis:subtle and contextual roles. Arterioscler Thromb Vasc Biol. 2015;35(2):258–264.
126. S.Chen, K.Shimada, W.Zhang, et al. IL-17A is proatherogenic in high-fat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice. J Immunol [Internet]. 2010;185(9):5619–5627. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20935201\nhttp://www.jimmunol.org/content/185/9/5619.full.pdf
127. C.Erbel, L.Chen, F.Bea, et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol. 2009;183(12):8167–8175.
128. X.Cheng, S.Taleb, J.Wang, et al. Inhibition of IL-17A in atherosclerosis. Atherosclerosis. 2011;215(2):471–474.
129. E.Smith, K.M.R.Prasad, M.Butcher, et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2010;121(15):1746–1755.
130. T.Van Es, G.H.M.Van Puijvelde, O.H.Ramos, et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun. 2009;388(2):261–265.
131. S.Taleb, M.Romain, B.Ramkhelawon, et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med [Internet]. 2009;206(10):2067–2077. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19737863
132. H.Ait-Oufella, O.Herbin, J.-D.Bouaziz, et al. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207(8):1579–1587.
133. K.Danzaki, Y.Matsui, M.Ikesue, et al. Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32(2):273–280.
134. C.Erbel, M.Akhavanpoor, D.Okuyucu, et al. IL-17A influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis. J Immunol [Internet]. 2014;193(9):4344–4355. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400181
135. K.Ghoreschi, A.Laurence, X.-P.Yang, et al. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol. 2011;32(9):395–401.
136. A.Gisterå, A.-K.L.Robertson, J.Andersson, et al. Transforming growth factor-β signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway. Sci Transl Med [Internet]. 2013;5(196):196ra100. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23903754
137. X.Cheng, X.Yu, Y.-J.Ding, et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol. 2008;127(1):89–97.
138. Z.Zhao, Y.Wu, M.Cheng, et al. Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis. 2011;217(2):518–524.
139. R.E.Eid, D.A.Rao, J.Zhou, et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation [Internet]. 2009;119(10):1424–1432. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19255340
140. T.Simon, S.Taleb, N.Danchin, et al. Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction. Eur Heart J. 2013;34(8):570–577.
141. M.S.Young, E.J.Horn, J.C.Cather. The ACCEPT study:ustekinumab versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin Immunol [Internet]. 2011;7(1):9–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21162644
142. P.J.Mease, I.B.McInnes, B.Kirkham, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med [Internet]. 2015;373(14):1329–1339. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa1412679
143. C.Ryan, C.L.Leonardi, J.G.Krueger, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events:a meta-analysis of randomized controlled trials. Jama. 2011;306(8):864–871.
144. J.L.Pastrana, X.Sha, A.Virtue, et al. Regulatory T cells and atherosclerosis. J Clin Exp Cardiolog [Internet]. 2012;2012(Suppl 12):2. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3757946&tool=pmcentrez&rendertype=abstract
145. O.J.De Boer, J.J.Van Der Meer, P.Teeling, et al. Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. Plos One [Internet]. 2007;2(8):e779. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17712427
146. E.Maganto-Garcia, M.L.Tarrio, N.Grabie, et al. Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation. 2011;124(2):185–195.
147. R.Gräbner, K.Lötzer, S.Döpping, et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med. 2009;206(1):233–248.
148. H.Ait-Oufella, B.L.Salomon, S.Potteaux, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med [Internet]. 2006;12(2):178–180. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16462800
149. S.Taleb, A.Tedgui, Z.Mallat. Regulatory T-cell immunity and its relevance to atherosclerosis. J Intern Med [Internet]. 2008;263(5):489–499. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18410592
150. C.Weber, S.Meiler, Y.Döring, et al. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121(7):2898–2910.
151. A.Nicoletti, G.Paulsson, G.Caligiuri, et al. Induction of neonatal tolerance to oxidized lipoprotein reduces atherosclerosis in ApoE knockout mice. Mol Med [Internet]. 2000;6(4):283–290. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1949951&tool=pmcentrez&rendertype=abstract\nhttp://www.scopus.com/inward/record.url?eid=2-s2.0-0034170821&partnerID=tZOtx3y1
152. H.Ait-Oufella, B.Horvat, Y.Kerdiles, et al. Measles virus nucleoprotein induces a regulatory immune response and reduces atherosclerosis in mice. Circulation [Internet]. 2007;116(15):1707–1713. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17875970
153. R.Klingenberg, M.Lebens, A.Hermansson, et al. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arter Thromb Vasc Biol. 2010;30(5):946–952.
154. X.Li, Z.Liu, X.Yan, et al. Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation. PLoS One. 2013;8(7):e68997.
155. O.Herbin, H.Ait-Oufella, W.Yu, et al. Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice. Arter Thromb Vasc Biol [Internet]. 2012;32(3):605–612. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22223728
156. C.Grundtman, B.Jakic, M.Buszko, et al. Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis:preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides. Atherosclerosis. 2015;242(1):303–310.
157. M.Steinmetz, P.Ponnuswamy, L.Laurans, et al. The intravenous injection of oxidized LDL- or apolipoprotein B100 - coupled splenocytes promotes Th1 polarization in wildtype and apolipoprotein E - deficient mice. Biochem Biophys Res Commun. 2015;464(1):306–311.
158. A.Hermansson, D.F.J.Ketelhuth, D.Strodthoff, et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med. 2010;207(5):1081–1093.
159. K.L.L.Habets, G.H.M.Van Puijvelde, L.M.Van Duivenvoorde, et al. Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice. Cardiovasc Res. 2010;85(3):622–630.
160. C.Hjerpe, D.Johansson, A.Hermansson, et al. Dendritic cells pulsed with malondialdehyde modified low density lipoprotein aggravate atherosclerosis in Apoe−/− mice. Atherosclerosis. 2010;209(2):436–441.
161. J.-H.Choi, C.Cheong, D.B.Dandamudi, et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity. 2011;35(5):819–831.
162. A.P.Sage, D.Murphy, P.Maffia, et al. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity. Circulation. 2014;130(16):1363–1373.
163. H.Ait-Oufella, A.P.Sage, Z.Mallat, et al. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res. 2014;114(10):1640–1660.
164. A.Hermansson, D.K.Johansson, D.F.J.Ketelhuth, et al. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation. 2011;123(10):1083–1091.
165. T.N.Dinh, T.S.Kyaw, P.Kanellakis, et al. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation. 2012;126(10):1256–1266.
166. T.Dietrich, T.Hucko, C.Schneemann, et al. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis. 2012;220(2):329–336.
167. A.Mor, G.Luboshits, D.Planer, et al. Altered status of CD4+CD25+ regulatory T cells in patients with acute coronary syndromes. Eur Heart J. 2006;27(21):2530–2537.
168. L.Hasib, A.K.Lundberg, H.Zachrisson, et al. Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease. J Intern Med. 2016;279(1):63–77.
169. T.Emoto, N.Sasaki, T.Yamashita, et al. Regulatory/effector T-cell ratio is reduced in coronary artery disease. Circ J [Internet]. 2014;78(12):2935–2941. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25327882
170. M.Wigren, H.Björkbacka, L.Andersson, et al. Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke. Arterioscler Thromb Vasc Biol. 2012;32(8):2000–2007.
171. B.Dietel, I.Cicha, C.J.Voskens, et al. Decreased numbers of regulatory T cells are associated with human atherosclerotic lesion vulnerability and inversely correlate with infiltrated mature dendritic cells. Atherosclerosis. 2013;230(1):92–99.
172. B.D.Singer, L.S.King, F.R.D’Alessio. Regulatory T cells as immunotherapy. Front Immunol. 2014;5(Feb):46.
173. N.Marek-Trzonkowska, M.Myśliwiec, A.Dobyszuk, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127(-) regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin Immunol [Internet]. 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24704576
174. P.Trzonkowski, M.Bieniaszewska, J.Juścińska, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells. Clin Immunol. 2009;133(1):22–26.
175. D.A.Chistiakov, I.A.Sobenin, A.N.Orekhov, et al. Dendritic cells in atherosclerotic inflammation:the complexity of functions and the peculiarities of pathophysiological effects. Front Physiol. 2014 May 5;196.
176. J.Koreth, K.Matsuoka, H.T.Kim, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med [Internet]. 2011;365(22):2055–2066. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22129252\nhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3727432
177. D.Saadoun, M.Rosenzwajg, F.Joly, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22):2067–2077.• References [176] and [177] highlight the safety and efficacy of low dose IL2 in increasing the number of Tregs and limiting exaggerated immune responses. Low dose IL2 therapy is one of the most promising strategy that could dampen detrimental immune responses in several settings of immune-mediated diseases, including cardiovascular disease.
178. P.Ponnuswamy, E.A.Van Vre, Z.Mallat, et al. Humoral and cellular immune responses in atherosclerosis:spotlight on B- and T-cells. Vasc Pharmacol [Internet]. 2012;56(5–6):193–203. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22329947
179. B.Paigen, A.Morrow, C.Brandon, et al. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis [Internet]. 1985;57(1):65–73. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3841001
180. S.A.Huber, P.Sakkinen, C.David, et al. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation. 2001;103(21):2610–2616.
181. V.L.King, S.J.Szilvassy, A.Daugherty. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice. Arterioscler Thromb Vasc Biol. 2002;22(3):456–461.
182. V.L.King, L.A.Cassis, A.Daugherty. Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice. Am J Pathol [Internet]. 2007;171(6):2040–2047. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2111126&tool=pmcentrez&rendertype=abstract
183. P.Davenport, P.G.Tipping. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol [Internet]. 2003;163(3):1117–1125. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1868277&tool=pmcentrez&rendertype=abstract
184. Y.Lin, Z.Chen, S.Kato. Receptor-selective IL-4 mutein modulates inflammatory vascular cell phenotypes and attenuates atherogenesis in apolipoprotein E-knockout mice. Exp Mol Pathol. 2015;99(1):116–127.
185. C.J.Binder, K.Hartvigsen, M.-K.Chang, et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest. 2004;114(3):427–437.
186. A.M.Miller, D.Xu, D.L.Asquith, et al. IL-33 reduces the development of atherosclerosis. J Exp Med [Internet]. 2008;205(2):339–346. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2271006&tool=pmcentrez&rendertype=abstract
187. L.Cardilo-Reis, S.Gruber, S.M.Schreier, et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med. 2012;4(10):1072–1086.
188. Z.Mallat, S.Besnard, M.Duriez, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res [Internet]. 1999;85(8):e17–e24. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10521249
189. K.Nishihira, T.Imamura, A.Yamashita, et al. Increased expression of interleukin-10 in unstable plaque obtained by directional coronary atherectomy. Eur Heart J. 2006;27(14):1685–1689.
190. E.Ammirati, F.Moroni, M.Magnoni, et al. The role of T and B cells in human atherosclerosis and atherothrombosis. Clin Exp Immunol [Internet]. 2015;179(2):173–187. Available from: http://onlinelibrary.wiley.com/doi/10.1111/cei.12477/abstract\nhttp://onlinelibrary.wiley.com.libaccess.lib.mcmaster.ca/doi/10.1111/cei.12477/abstract\nhttp://onlinelibrary.wiley.com.libaccess.lib.mcmaster.ca/store/10.1111/cei.12477/asset/cei12477.pdf?v=1
191. H.C.Jha, A.Divya, J.Prasad, et al. Plasma circulatory markers in male and female patients with coronary artery disease. Heart Lung [Internet]. 2010;39(4):296–303. doi:10.1016/j.hrtlng.2009.10.005.
192. S.R.Mirhafez, A.Zarifian, M.Ebrahimi, et al. Relationship between serum cytokine and growth factor concentrations and coronary artery disease. Clin Biochem. 2015;48(9):575–580.
193. T.Ibc, C.A.D.Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 2011;7(9):e1002260.
194. M.Sampi, O.Ukkola, M.Paivansalo, et al. Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis. J Am Coll Cardiol. 2008;52(17):1370–1378.
195. A.Silveira, O.McLeod, R.J.Strawbridge, et al. Plasma IL-5 concentration and subclinical carotid atherosclerosis. Atherosclerosis. 2015;239(1):125–130.
196. O.McLeod, A.Silveira, E.Valdes-Marquez, et al. Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease. Cytokine. 2016;81:1–9.
197. T.Ishigami, K.Abe, I.Aoki, et al. Anti-interleukin-5 and multiple autoantibodies are associated with human atherosclerotic diseases and serum interleukin-5 levels. Faseb J. 2013;27(9):3437–3445.
198. G.Garcia, C.Taillé, P.Laveneziana, et al. Anti-interleukin-5 therapy in severe asthma. Eur Respir Rev. 2013;22(129):251–257.
199. F.Van Gool, A.B.Molofsky, M.M.Morar, et al. Interleukin-5 - producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood. 2014;124(24):3572–3576.
200. E.A.Fisher. Regression of atherosclerosis:the journey from the liver to the plaque and back. Arterioscler Thromb Vasc Biol. 2016;36(2):226–235.