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Novel Immune Signals and Atherosclerosis

  • Clinical Trials and Their Interpretations (J Plutzky, Section Editor)
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Abstract

Atherosclerosis underlies coronary artery disease (CAD) and cerebrovascular disease, which are the most common forms of life-threatening cardiovascular disorders. To minimize the risk of atherosclerotic complications, primary and secondary prevention strategies seek to control risk factors. Reducing low-density lipoprotein (LDL) cholesterol through lipid-lowering drugs, such as statins, in particular yields a proportional decrease in cardiovascular disease risk. Atherosclerosis is considered to be a complex chronic inflammatory process triggered by cardiovascular risk factors which cause endothelial dysfunction and inflammatory cell infiltration within the artery wall. In this review, we summarize the current understanding of the underling molecular mechanisms of the immune signals in the development and progression of atherosclerosis. Among various molecular mechanisms, toll like receptors (TLRs) are potent proinflammatory cytokines that operate to induce inflammation play an important role in the pathogenesis of atherosclerosis. Moreover, we discuss current knowledge regarding monocyte/macrophage biology that contributes to the progression of atherosclerosis, including macrophage polarization and heterogeneity. Understanding the molecular mechanisms in conjunction with orchestration of monocyte/macrophage biology should provide a basis for novel treatment strategies to prevent the development and progression of atherosclerosis.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science. 1973;180:1332–9.

    Article  PubMed  CAS  Google Scholar 

  2. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89:763–71.

    Article  PubMed  CAS  Google Scholar 

  3. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40.

    Article  PubMed  Google Scholar 

  4. Ridker PM. The time for cardiovascular inflammation reduction trials has arrived: how low to go for hscrp? Arterioscler Thromb Vasc Biol. 2008;28:1222–4.

    Article  PubMed  CAS  Google Scholar 

  5. Rubin J, Chang HJ, Nasir K, Blumenthal RS, Blaha MJ, Choi EK, et al. Association between high-sensitivity c-reactive protein and coronary plaque subtypes assessed by 64-slice coronary computed tomography angiography in an asymptomatic population. Circ Cardiovasc Imaging. 2011;4:201–9.

    Article  PubMed  Google Scholar 

  6. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med. 2008;359:2195–207.

    Article  PubMed  CAS  Google Scholar 

  7. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, et al. Monocyte subsets differentially employ ccr2, ccr5, and cx3cr1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–94.

    Article  PubMed  CAS  Google Scholar 

  8. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–81.

    Article  PubMed  CAS  Google Scholar 

  9. • Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204–12. A comprehensive, detailed and updated.review of immune system in atherosclerosis.

    Article  PubMed  CAS  Google Scholar 

  10. Yvan-Charvet L, Ranalletta M, Wang N, Han S, Terasaka N, Li R, et al. Combined deficiency of abca1 and abcg1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest. 2007;117:3900–8.

    PubMed  CAS  Google Scholar 

  11. Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001;104:503–16.

    Article  PubMed  CAS  Google Scholar 

  12. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10:36–46.

    Article  PubMed  CAS  Google Scholar 

  13. Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol. 2006;1:297–329.

    Article  PubMed  CAS  Google Scholar 

  14. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832–44.

    Article  PubMed  CAS  Google Scholar 

  15. Eriksson EE, Xie X, Werr J, Thoren P, Lindbom L. Importance of primary capture and l-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med. 2001;194:205–18.

    Article  PubMed  CAS  Google Scholar 

  16. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of vcam-1 and icam-1 at atherosclerosis-prone sites on the endothelium in the apoe-deficient mouse. Arterioscler Thromb Vasc Biol. 1998;18:842–51.

    Article  PubMed  CAS  Google Scholar 

  17. Dje N'Guessan P, Riediger F, Vardarova K, Scharf S, Eitel J, Opitz B, et al. Statins control oxidized ldl-mediated histone modifications and gene expression in cultured human endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:380–6.

    Article  PubMed  Google Scholar 

  18. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein e. Proc Natl Acad Sci USA. 1995;92:8264–8.

    Article  PubMed  CAS  Google Scholar 

  19. Bianchi ME. Damps, pamps and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.

    Article  PubMed  CAS  Google Scholar 

  20. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20.

    Article  PubMed  CAS  Google Scholar 

  21. Cole JE, Mitra AT, Monaco C. Treating atherosclerosis: the potential of toll-like receptors as therapeutic targets. Expert Rev Cardiovasc Ther. 2010;8:1619–35.

    Article  PubMed  CAS  Google Scholar 

  22. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11:373–84.

    Article  PubMed  CAS  Google Scholar 

  23. Seneviratne AN, Sivagurunathan B, Monaco C. Toll-like receptors and macrophage activation in atherosclerosis. Clin Chim Acta. 2012;413:3–14.

    Article  PubMed  CAS  Google Scholar 

  24. Cole JE, Georgiou E, Monaco C. The expression and functions of toll-like receptors in atherosclerosis. Mediators Inflamm. 2010;2010:393946.

  25. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA. 1995;92:3893–7.

    Article  PubMed  CAS  Google Scholar 

  26. Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A. The toll-like receptor repertoire of human b lymphocytes: inducible and selective expression of tlr9 and tlr10 in normal and transformed cells. Blood. 2003;102:956–63.

    Article  PubMed  Google Scholar 

  27. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, et al. Quantitative expression of toll-like receptor 1-10 mrna in cellular subsets of human peripheral blood mononuclear cells and sensitivity to cpg oligodeoxynucleotides. J Immunol. 2002;168:4531–7.

    PubMed  CAS  Google Scholar 

  28. Mansson A, Adner M, Hockerfelt U, Cardell LO. A distinct toll-like receptor repertoire in human tonsillar b cells, directly activated by pamcsk, r-837 and cpg-2006 stimulation. Immunology. 2006;118:539–48.

    PubMed  Google Scholar 

  29. Wagner M, Poeck H, Jahrsdoerfer B, Rothenfusser S, Prell D, Bohle B, et al. Il-12p70-dependent th1 induction by human b cells requires combined activation with cd40 ligand and cpg DNA. J Immunol. 2004;172:954–63.

    PubMed  CAS  Google Scholar 

  30. Lee JG, Lim EJ, Park DW, Lee SH, Kim JR, Baek SH. A combination of lox-1 and nox1 regulates tlr9-mediated foam cell formation. Cell Signal. 2008;20:2266–75.

    Article  PubMed  CAS  Google Scholar 

  31. Doyle SE, O'Connell RM, Miranda GA, Vaidya SA, Chow EK, Liu PT, et al. Toll-like receptors induce a phagocytic gene program through p38. J Exp Med. 2004;199:81–90.

    Article  PubMed  CAS  Google Scholar 

  32. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, et al. Cd36 is a sensor of diacylglycerides. Nature. 2005;433:523–7.

    Article  PubMed  CAS  Google Scholar 

  33. Triantafilou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, et al. Membrane sorting of toll-like receptor (tlr)-2/6 and tlr2/1 heterodimers at the cell surface determines heterotypic associations with cd36 and intracellular targeting. J Biol Chem. 2006;281:31002–11.

    Article  PubMed  CAS  Google Scholar 

  34. Jeannin P, Bottazzi B, Sironi M, Doni A, Rusnati M, Presta M, et al. Complexity and complementarity of outer membrane protein a recognition by cellular and humoral innate immunity receptors. Immunity. 2005;22:551–60.

    Article  PubMed  CAS  Google Scholar 

  35. Elhage R, Jawien J, Rudling M, Ljunggren HG, Takeda K, Akira S, et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein e-knockout mice. Cardiovasc Res. 2003;59:234–40.

    Article  PubMed  CAS  Google Scholar 

  36. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U. Expression of interleukin (il)-18 and functional il-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002;195:245–57.

    Article  PubMed  CAS  Google Scholar 

  37. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in apoe-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:656–60.

    Article  PubMed  CAS  Google Scholar 

  38. Foks AC, Frodermann V, ter Borg M, Habets KL, Bot I, Zhao Y, et al. Differential effects of regulatory t cells on the initiation and regression of atherosclerosis. Atherosclerosis. 2011;218:53–60.

    Article  PubMed  CAS  Google Scholar 

  39. Gotsman I, Grabie N, Gupta R, Dacosta R, MacConmara M, Lederer J, et al. Impaired regulatory t-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation. 2006;114:2047–55.

    Article  PubMed  CAS  Google Scholar 

  40. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449:419–26.

    Article  PubMed  CAS  Google Scholar 

  41. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.

    Article  PubMed  CAS  Google Scholar 

  42. Stoger JL, Goossens P, de Winther MP. Macrophage heterogeneity: relevance and functional implications in atherosclerosis. Curr Vasc Pharmacol. 2010;8:233–48.

    Article  PubMed  Google Scholar 

  43. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.

    Article  PubMed  CAS  Google Scholar 

  44. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, et al. Ly-6chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117:195–205.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in ccr2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894–7.

    Article  PubMed  CAS  Google Scholar 

  47. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669–92.

    Article  PubMed  CAS  Google Scholar 

  48. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.

    Article  PubMed  CAS  Google Scholar 

  49. Rothe G, Gabriel H, Kovacs E, Klucken J, Stohr J, Kindermann W, et al. Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1996;16:1437–47.

    Article  PubMed  CAS  Google Scholar 

  50. • 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. This is the interesting clinical study demonstrating the significant relationship between proportion of a specific subgroup of monocytes (CD14+CD16+) and clinical outcomes in the patients with acute myocardial infarction.

    Article  PubMed  Google Scholar 

  51. Wildgruber M, Lee H, Chudnovskiy A, Yoon TJ, Etzrodt M, Pittet MJ, et al. Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors. PLoS One. 2009;4:e5663.

    Article  PubMed  Google Scholar 

  52. Remy-Martin JP, Marandin A, Challier B, Bernard G, Deschaseaux M, Herve P, et al. Vascular smooth muscle differentiation of murine stroma: a sequential model. Exp Hematol. 1999;27:1782–95.

    Article  PubMed  CAS  Google Scholar 

  53. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002;8:403–9.

    Article  PubMed  CAS  Google Scholar 

  54. Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation. 2002;106:1199–204.

    Article  PubMed  CAS  Google Scholar 

  55. Iwata H, Manabe I, Fujiu K, Yamamoto T, Takeda N, Eguchi K, et al. Bone marrow-derived cells contribute to vascular inflammation but do not differentiate into smooth muscle cell lineages. Circulation. 2010;122:2048–57.

    Article  PubMed  CAS  Google Scholar 

  56. Bellini A, Mattoli S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest. 2007;87:858–70.

    Article  PubMed  CAS  Google Scholar 

  57. Greaves DR, Gordon S. The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. J Lipid Res. 2009;50(Suppl):S282–6.

    Article  PubMed  Google Scholar 

  58. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303–11.

    PubMed  CAS  Google Scholar 

  59. Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via nrf2. Circ Res. 2010;107:737–46.

    Article  PubMed  CAS  Google Scholar 

  60. Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C. Innate immunity and monocyte-macrophage activation in atherosclerosis. J Inflamm (Lond). 2011;8:9.

    Article  CAS  Google Scholar 

  61. Boyle JJ, Johns M, Kampfer T, Nguyen AT, Game L, Schaer DJ, et al. Activating transcription factor 1 directs mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res. 2012;110:20–33.

    Article  PubMed  CAS  Google Scholar 

  62. Butcher MJ, Galkina EV. Phenotypic and functional heterogeneity of macrophages and dendritic cell subsets in the healthy and atherosclerosis-prone aorta. Front Physiol. 2012;3:44.

    Article  PubMed  CAS  Google Scholar 

  63. Gleissner CA. Macrophage phenotype modulation by cxcl4 in atherosclerosis. Front Physiol. 2012;3:1.

    Article  PubMed  CAS  Google Scholar 

  64. Kirbis S, Breskvar UD, Sabovic M, Zupan I, Sinkovic A. Inflammation markers in patients with coronary artery disease–comparison of intracoronary and systemic levels. Wien Klin Wochenschr. 2010;122 Suppl 2:31–4.

    Article  PubMed  CAS  Google Scholar 

  65. Savchenko A, Imamura M, Ohashi R, Jiang S, Kawasaki T, Hasegawa G, et al. Expression of pentraxin 3 (ptx3) in human atherosclerotic lesions. J Pathol. 2008;215:48–55.

    Article  PubMed  CAS  Google Scholar 

  66. Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, et al. Macrophage plasticity in experimental atherosclerosis. PLoS One. 2010;5:e8852.

    Article  PubMed  Google Scholar 

  67. Aliev G, Smith MA, Turmaine M, Neal ML, Zimina TV, Friedland RP, et al. Atherosclerotic lesions are associated with increased immunoreactivity for inducible nitric oxide synthase and endothelin-1 in thoracic aortic intimal cells of hyperlipidemic watanabe rabbits. Exp Mol Pathol. 2001;71:40–54.

    Article  PubMed  CAS  Google Scholar 

  68. Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001;89:930–4.

    Article  PubMed  CAS  Google Scholar 

  69. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  PubMed  CAS  Google Scholar 

  70. Thorp E, Tabas I. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol. 2009;86:1089–95.

    Article  PubMed  CAS  Google Scholar 

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Sources of Funding

This study was supported by the Japan Society for the Promotion of Science (JSPS) through its “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) and grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology (21790709 to H.I.).

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Authors and Affiliations

  1. Brigham and Women’s Hospital, Department of Medicine, Cardiovascular Division, Center for Interdisciplinary Cardiovascular Sciences, 3 Blackfan Street, 17th Floor, Boston, MA, 02115, USA

    Hiroshi Iwata

  2. Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi Prefecture, Japan, 329-0498

    Ryozo Nagai

  3. Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan

    Hiroshi Iwata & Ryozo Nagai

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  1. Hiroshi Iwata
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Correspondence to Hiroshi Iwata.

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Iwata, H., Nagai, R. Novel Immune Signals and Atherosclerosis. Curr Atheroscler Rep 14, 484–490 (2012). https://doi.org/10.1007/s11883-012-0267-7

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