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Beyond vascular inflammation—recent advances in understanding atherosclerosis

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Abstract

Atherosclerosis is the most life-threatening pathology worldwide. Its major clinical complications, stroke, myocardial infarction, and heart failure, are on the rise in many regions of the world—despite considerable progress in understanding cause, progression, and consequences of atherosclerosis. Originally perceived as a lipid-storage disease of the arterial wall (Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. August Hirschwald Verlag Berlin, [1871]), atherosclerosis was recognized as a chronic inflammatory disease in 1986 (New Engl J Med 314:488-500, 1986). The presence of lymphocytes in atherosclerotic lesions suggested autoimmune processes in the vessel wall (Clin Exp Immunol 64:261–268, 1986). Since the advent of suitable mouse models of atherosclerosis (Science 258:468–471, 1992; Cell 71:343-353, 1992; J Clin Invest 92:883–893, 1993) and the development of flow cytometry to define the cellular infiltrate in atherosclerotic lesions (J Exp Med 203:1273–1282, 2006), the origin, lineage, phenotype, and function of distinct inflammatory cells that trigger or inhibit the inflammatory response in the atherosclerotic plaque have been studied. Multiphoton microscopy recently enabled direct visualization of antigen-specific interactions between T cells and antigen-presenting cells in the vessel wall (J Clin Invest 122:3114–3126, 2012). Vascular immunology is now emerging as a new field, providing evidence for protective as well as damaging autoimmune responses (Int Immunol 25:615–622, 2013). Manipulating inflammation and autoimmunity both hold promise for new therapeutic strategies in cardiovascular disease. Ongoing work (J Clin Invest 123:27–36, 2013; Front Immunol 2013; Semin Immunol 31:95–101, 2009) suggests that it may be possible to develop antigen-specific immunomodulatory prevention and therapy—a vaccine against atherosclerosis.

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References

  1. Virchow R (1859) Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. Verlag von August Hirschwald, Berlin

  2. Ross R (1986) The pathogenesis of atherosclerosis–an update. New Engl J Med 314:488–500

    Article  CAS  PubMed  Google Scholar 

  3. Hansson GK, Jonasson L, Holm J, Claesson-Welsh L (1986) Class ii mhc antigen expression in the atherosclerotic plaque: smooth muscle cells express hla-dr, hla-dq and the invariant gamma chain. Clin Exp Immunol 64:261–268

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein e. Science 258:468–471

    Article  CAS  PubMed  Google Scholar 

  5. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein e-deficient mice created by homologous recombination in es cells. Cell 71:343–353

    Article  CAS  PubMed  Google Scholar 

  6. Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J (1993) Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 92:883–893

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ, Ley K (2006) Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially l-selectin dependent. J Exp Med 203:1273–1282

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Koltsova EK, Garcia Z, Chodaczek G, Landau M, McArdle S, Scott SR, von Vietinghoff S, Galkina E, Miller YI, Acton ST, Ley K (2012) Dynamic t cell-apc interactions sustain chronic inflammation in atherosclerosis. J Clin Invest 122:3114–3126

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Tse K, Tse H, Sidney J, Sette A, Ley K (2013) T cells in atherosclerosis. Int Immunol 25:615–622

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Lichtman AH, Binder CJ, Tsimikas S, Witztum JL (2013) Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 123:27–36

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, Tse H, Ley K (2013) Atheroprotective vaccination with mhc-ii restricted peptides from apob-100. Front Immunol 4:493

  12. Hansson GK, Nilsson J (2009) Vaccination against atherosclerosis? Induction of atheroprotective immunity. Semin Immunopathol 31:95–101

    Article  CAS  PubMed  Google Scholar 

  13. Ley K, Miller YI, Hedrick CC (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31:1506–1516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Koltsova EK, Hedrick CC, Ley K (2013) Myeloid cells in atherosclerosis: a delicate balance of anti-inflammatory and proinflammatory mechanisms. Curr Opin Lipidol 24:371–380

    CAS  PubMed  Google Scholar 

  15. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol 27:165–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Spann NJ, Garmire LX, McDonald JG et al (2012) Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151:138–152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R (2010) Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 30:1282–1292

    Article  CAS  PubMed  Google Scholar 

  19. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874

    Article  CAS  PubMed  Google Scholar 

  20. Galis ZS, Sukhova GK, Lark MW, Libby P (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Newby AC (2015) Metalloproteinases promote plaque rupture and myocardial infarction: a persuasive concept waiting for clinical translation. Matrix Biol 44–46C:157–166

    Article  CAS  Google Scholar 

  22. van Furth R (1970) Origin and kinetics of monocytes and macrophages. Semin Hematol 7:125–141

    PubMed  Google Scholar 

  23. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Sieweke MH, Allen JE (2013) Beyond stem cells: self-renewal of differentiated macrophages. Science 342:1242974

    Article  PubMed  CAS  Google Scholar 

  25. Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P, Weissleder R (2006) Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci USA 103:10340–10345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ ccr2, ccr5, and cx3cr1 to accumulate within atherosclerotic plaques. J Clin Invest 117:185–194

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Gerrity RG (1981) The role of the monocyte in atherogenesis: I. transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol 103:181–190

    PubMed Central  CAS  PubMed  Google Scholar 

  29. McArdle S, Chodaczek G, Ray N, Ley K (2015) Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries. J Biomed Optics 20:26005

    Article  CAS  Google Scholar 

  30. Nagareddy PR, Murphy AJ, Stirzaker RA et al (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695–708

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L, Tall AR (2011) Apoe regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 121:4138–4149

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Heidt T, Sager HB, Courties G et al (2014) Chronic variable stress activates hematopoietic stem cells. Nat Med 20:754–758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Dutta P, Courties G, Wei Y et al (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Wolf D, Ley K (2015) Waking up the stem cell niche: how hematopoietic stem cells generate inflammatory monocytes after stroke. Circ Res 116:389–392

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Leuschner F, Rauch PJ, Ueno T et al (2012) Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med 209:123–137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Swirski FK, Nahrendorf M, Etzrodt M et al (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Jakubzick C, Gautier EL, Gibbings SL et al (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39:599–610

    Article  CAS  PubMed  Google Scholar 

  38. Guo J, de Waard V, Van Eck M, Hildebrand RB, van Wanrooij EJ, Kuiper J, Maeda N, Benson GM, Groot PH, Van Berkel TJ (2005) Repopulation of apolipoprotein e knockout mice with ccr2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development. Arterioscler Thromb Vasc Biol 25:1014–1019

    Article  CAS  PubMed  Google Scholar 

  39. Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689

    Article  CAS  PubMed  Google Scholar 

  40. Stoneman V, Braganza D, Figg N, Mercer J, Lang R, Goddard M, Bennett M (2007) Monocyte/macrophage suppression in cd11b diphtheria toxin receptor transgenic mice differentially affects atherogenesis and established plaques. Circ Res 100:884–893

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Gordon D, Reidy MA, Benditt EP, Schwartz SM (1990) Cell proliferation in human coronary arteries. Proc Natl Acad Sci USA 87:4600–4604

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Lutgens E, de Muinck ED, Kitslaar PJ, Tordoir JH, Wellens HJ, Daemen MJ (1999) Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques. Cardiovasc Res 41:473–479

    Article  CAS  PubMed  Google Scholar 

  43. Rosenfeld ME, Ross R (1990) Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of whhl and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 10:680–687

    Article  CAS  PubMed  Google Scholar 

  44. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, MacDonald AS, Allen JE (2011) Local macrophage proliferation, rather than recruitment from the blood, is a signature of th2 inflammation. Science 332:1284–1288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hashimoto D, Chow A, Noizat C et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804

    Article  CAS  PubMed  Google Scholar 

  46. Robbins CS, Hilgendorf I, Weber GF et al (2013) Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166–1172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM, McKee M, Freeman MW (2005) Loss of receptor-mediated lipid uptake via scavenger receptor a or cd36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 115:2192–2201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, Alvarez-Leite JI, de Winther MP, Tabas I, Freeman MW (2009) Loss of sr-a and cd36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol 29:19–26

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Makinen PI, Lappalainen JP, Heinonen SE, Leppanen P, Lahteenvuo MT, Aarnio JV, Heikkila J, Turunen MP, Yla-Herttuala S (2010) Silencing of either sr-a or cd36 reduces atherosclerosis in hyperlipidaemic mice and reveals reciprocal upregulation of these receptors. Cardiovasc Res 88:530–538

    Article  PubMed  CAS  Google Scholar 

  50. Heidt T, Courties G, Dutta P, Sager HB, Sebas M, Iwamoto Y, Sun Y, Da Silva N, Panizzi P, van der Laan AM, Swirski FK, Weissleder R, Nahrendorf M (2014) Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 115:284–295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Hilgendorf I, Swirski FK, Robbins CS (2015) Monocyte fate in atherosclerosis. Arterioscler Thromb Vasc Biol 35:272–279

    Article  CAS  PubMed  Google Scholar 

  52. Perdiguero EG, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR (2014) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature

  53. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41:21–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Randolph GJ (2014) A macrophage revolution-and beyond. Immunol Rev 262:5–8

    Article  PubMed  Google Scholar 

  55. Yona S, Kim KW, Wolf Y et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Schulz C (2012) Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F. A lineage of myeloid cells independent of myb and hematopoietic stem cells. Science 336:86–90

    Article  CAS  PubMed  Google Scholar 

  57. Epelman S, Lavine KJ, Beaudin AE et al (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN (2014) Macrophages are required for neonatal heart regeneration. J Clin Invest. 124:1382–1392

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Allahverdian S, Pannu PS, Francis GA (2012) Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation. Cardiovasc Res 95:165–172

    Article  CAS  PubMed  Google Scholar 

  60. Rong JX, Shapiro M, Trogan E, Fisher EA (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci USA. 100:13531–13536

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Feil S, Fehrenbacher B, Lukowski R, Essmann F, Schulze-Osthoff K, Schaller M, Feil R (2014) Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 115:662–667

    Article  CAS  PubMed  Google Scholar 

  62. Nguyen AT, Gomez D, Bell RD et al (2013) Smooth muscle cell plasticity: fact or fiction? Circ Res 112:17–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Vengrenyuk Y, Nishi H, Long X, Ouimet M, Savji N, Martinez FO, Cassella CP, Moore KJ, Ramsey SA, Miano JM, Fisher EA (2015) Cholesterol loading reprograms the microrna-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol 35:535–546

    Article  CAS  PubMed  Google Scholar 

  64. Randolph GJ (2014) Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 114:1757–1771

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA 101:11779–11784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P, Raichlen JS, Uno K, Borgman M, Wolski K, Nissen SE (2011) Effect of two intensive statin regimens on progression of coronary disease. New Engl J Med 365:2078–2087

    Article  CAS  PubMed  Google Scholar 

  67. Raffai RL, Loeb SM, Weisgraber KH (2005) Apolipoprotein e promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Arterioscler Thromb Vasc Biol 25:436–441

    Article  CAS  PubMed  Google Scholar 

  68. Zeng H, Horie K, Madisen L et al (2008) An inducible and reversible mouse genetic rescue system. PLoS Genet 4:e1000069

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Gautier EL, Huby T, Witztum JL, Ouzilleau B, Miller ER, Saint-Charles F, Aucouturier P, Chapman MJ, Lesnik P (2009) Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation 119:1795–1804

    Article  CAS  PubMed  Google Scholar 

  71. Bellingan GJ, Caldwell H, Howie SE, Dransfield I, Haslett C (1996) In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 157:2577–2585

    CAS  PubMed  Google Scholar 

  72. Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, Wanschel A, Oldebeken S, Geoffrion M, Spiro W, Miller G, McPherson R, Rayner KJ, Moore KJ (2014) Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 20:377–384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Trogan E, Feig JE, Dogan S, Rothblat GH, Angeli V, Tacke F, Randolph GJ, Fisher EA (2006) Gene expression changes in foam cells and the role of chemokine receptor ccr7 during atherosclerosis regression in apoe-deficient mice. Proc Natl Acad Sci USA 103:3781–3786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ (2011) Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of apoe−/− mice during disease regression. J Clin Invest 121:2025–2036

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Gautier EL, Ivanov S, Lesnik P, Randolph GJ (2013) Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Blood 122:2714–2722

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/m-2 macrophages and the th1/th2 paradigm. J Immunol 164:6166–6173

    Article  CAS  PubMed  Google Scholar 

  77. Mills CD, Ley K (2014) M1 and m2 macrophages: the chicken and the egg of immunity. J Innate Immunity 6:716–726

    Article  CAS  Google Scholar 

  78. Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Martinez FO, Gordon S, Locati M, Mantovani A (2006) Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 177:7303–7311

    Article  CAS  PubMed  Google Scholar 

  80. Leitinger N, Schulman IG (2013) Phenotypic polarization of macrophages in atherosclerosis. Arterioscler Thromb Vasc Biol 33:1120–1126

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Duewell P, Kono H, Rayner KJ et al (2010) Nlrp3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Hanna RN, Shaked I, Hubbeling HG, Punt JA, Wu R, Herrley E, Zaugg C, Pei H, Geissmann F, Ley K, Hedrick CC (2012) Nr4a1 (nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res 110:416–427

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Kadl A, Meher AK, Sharma PR et al (2010) Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via nrf2. Circ Res 107:737–746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Gleissner CA, Shaked I, Little KM, Ley K (2010) Cxc chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 184:4810–4818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Gleissner CA, Shaked I, Erbel C, Bockler D, Katus HA, Ley K (2010) Cxcl4 downregulates the atheroprotective hemoglobin receptor cd163 in human macrophages. Circ Res 106:203–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Fleming BD, Mosser DM (2011) Regulatory macrophages: setting the threshold for therapy. Eur J Immunol 41:2498–2502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA, Delacroix S, Kleppe LS, Mueske CS, Pan S, Gulati R, Simari RD (2014) Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res 115:364–375

    Article  CAS  PubMed  Google Scholar 

  89. Erbel C, Tyka M, Helmes CM, Akhavanpoor M, Rupp G, Domschke G, Linden F, Wolf A, Doesch A, Lasitschka F, Katus HA, Gleissner CA (2015) Cxcl4-induced plaque macrophages can be specifically identified by co-expression of mmp7+ s100a8+ in vitro and in vivo. Innate Immunity 21:255–265

    Article  CAS  PubMed  Google Scholar 

  90. Hayes EM, Tsaousi A, Di Gregoli K, Jenkinson SR, Bond AR, Johnson JL, Bevan L, Thomas AC, Newby AC (2014) Classical and alternative activation and metalloproteinase expression occurs in foam cell macrophages in male and female apoe null mice in the absence of t and b lymphocytes. Front Immunol 5:537

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  91. Boyle JJ (2012) Heme and haemoglobin direct macrophage mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol 23:453–461

    Article  PubMed  CAS  Google Scholar 

  92. Stoger JL, Gijbels MJ, van der Velden S, Manca M, van der Loos CM, Biessen EA, Daemen MJ, Lutgens E, de Winther MP (2012) Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis 225:461–468

    Article  PubMed  CAS  Google Scholar 

  93. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P (1995) Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann NY Acad Sci 748:501–507

    Article  CAS  PubMed  Google Scholar 

  94. Huang WC, Sala-Newby GB, Susana A, Johnson JL, Newby AC (2012) Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-kappab. PLoS One 7:e42507

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Johnson JL, Jenkins NP, Huang WC, Di Gregoli K, Sala-Newby GB, Scholtes VP, Moll FL, Pasterkamp G, Newby AC (2014) Relationship of mmp-14 and timp-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Mediators Inflamm 2014:276457

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  96. Courties G, Heidt T, Sebas M et al (2014) In vivo silencing of the transcription factor irf5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol 63:1556–1566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Watkins AA, Yasuda K, Wilson GE et al (2015) Irf5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis. J Immunol 194:1467–1479

    Article  CAS  PubMed  Google Scholar 

  98. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK (2014) Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159:1327–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159:1312–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Mancinelli E, Lauvau G (2008) Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of t-cell responses. Immunol Cell Biol 86:398–408

    Article  CAS  PubMed  Google Scholar 

  101. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt JA, Geissmann F, Hedrick CC (2011) The transcription factor nr4a1 (nur77) controls bone marrow differentiation and the survival of ly6c- monocytes. Nat Immunol 12:778–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Majmudar MD, Keliher EJ, Heidt T et al (2013) Monocyte-directed rnai targeting ccr2 improves infarct healing in atherosclerosis-prone mice. Circulation 127:2038–2046

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Bonta PI, van Tiel CM, Vos M, Pols TW, van Thienen JV, Ferreira V, Arkenbout EK, Seppen J, Spek CA, van der Poll T, Pannekoek H, de Vries CJ (2006) Nuclear receptors nur77, nurr1, and nor-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler Thromb Vasc Biol 26:2288–2294

    Article  CAS  PubMed  Google Scholar 

  104. Ramachandran P, Pellicoro A, Vernon MA et al (2012) Differential ly-6c expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci USA 109:E3186–E3195

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Varol C, Yona S, Jung S (2009) Origins and tissue-context-dependent fates of blood monocytes. Immunol Cell Biol 87:30–38

    Article  PubMed  CAS  Google Scholar 

  106. Sakai M, Miyazaki A, Hakamata H, Sasaki T, Yui S, Yamazaki M, Shichiri M, Horiuchi S (1994) Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem 269:31430–31435

    CAS  PubMed  Google Scholar 

  107. Bain CC, Bravo-Blas A, Scott CL (2014) Gomez Perdiguero E, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15:929–937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Randolph GJ (2013) Proliferating macrophages prevail in atherosclerosis. Nat Med 19:1094–1095

    Article  CAS  PubMed  Google Scholar 

  109. Majesky MW, Dong XR, Hoglund V, Daum G, Mahoney WM Jr (2012) The adventitia: a progenitor cell niche for the vessel wall. Cells Tissues Organs 195:73–81

    Article  PubMed  Google Scholar 

  110. Kimura T, Tse K, Sette A, Ley K (2015) Vaccination to modulate atherosclerosis. Autoimmunity 48:152–160

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK (1986) Regional accumulations of t cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6:131–138

    Article  CAS  PubMed  Google Scholar 

  112. Robertson AK, Hansson GK (2006) T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol 26:2421–2432

    Article  CAS  PubMed  Google Scholar 

  113. Buono C, Binder CJ, Stavrakis G, Witztum JL, Glimcher LH, Lichtman AH (2005) T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci USA 102:1596–1601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Buono C, Come CE, Stavrakis G, Maguire GF, Connelly PW, Lichtman AH (2003) Influence of interferon-gamma on the extent and phenotype of diet-induced atherosclerosis in the ldlr-deficient mouse. Arterioscler Thromb Vasc Biol 23:454–460

    Article  CAS  PubMed  Google Scholar 

  115. Gupta S, Pablo AM, Jiang X, Wang N, Tall AR, Schindler C (1997) Ifn-gamma potentiates atherosclerosis in apoe knock-out mice. J Clin Invest 99:2752–2761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Erbel C, Akhavanpoor M, Okuyucu D et al (2014) Il-17a influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis. J Immunol 193:4344–4355

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Davenport P, Tipping PG (2003) The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein e-deficient mice. Am J Pathol 163:1117–1125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. King VL, Cassis LA, Daugherty A (2007) Interleukin-4 does not influence development of hypercholesterolemia or angiotensin ii-induced atherosclerotic lesions in mice. Am J Pathol 171:2040–2047

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Cheng X, Taleb S, Wang J et al (2010) Inhibition of il-17a in atherosclerosis. Atherosclerosis 215:471–474

    Article  CAS  Google Scholar 

  120. Danzaki K, Matsui Y, Ikesue M, Ohta D, Ito K, Kanayama M, Kurotaki D, Morimoto J, Iwakura Y, Yagita H, Tsutsui H, Uede T (2012) Interleukin-17a deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol 32:273–280

    Article  CAS  PubMed  Google Scholar 

  121. Erbel C, Chen L, Bea F, Wangler S, Celik S, Lasitschka F, Wang Y, Bockler D, Katus HA, Dengler TJ (2009) Inhibition of il-17a attenuates atherosclerotic lesion development in apoe-deficient mice. J Immunol 183:8167–8175

    Article  CAS  PubMed  Google Scholar 

  122. Gao Q, Jiang Y, Ma T, Zhu F, Gao F, Zhang P, Guo C, Wang Q, Wang X, Ma C, Zhang Y, Chen W, Zhang L A critical function of th17 proinflammatory cells in the development of atherosclerotic plaque in mice. J Immunol. 185:5820–5827

  123. Butcher MJ, Gjurich BN, Phillips T, Galkina EV (2012) The il-17a/il-17ra axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment. Circ Res 110:675–687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Smith E, Prasad KM, Butcher M, Dobrian A, Kolls JK, Ley K, Galkina E (2010) Blockade of interleukin-17a results in reduced atherosclerosis in apolipoprotein e-deficient mice. Circulation 121:1746–1755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. De Palma R, Del Galdo F, Abbate G et al (2006) Patients with acute coronary syndrome show oligoclonal t-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 113:640–646

    Article  PubMed  Google Scholar 

  126. Paulsson G, Zhou X, Tornquist E, Hansson GK (2000) Oligoclonal t cell expansions in atherosclerotic lesions of apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol 20:10–17

    Article  CAS  PubMed  Google Scholar 

  127. Ketelhuth DF, Hansson GK (2011) Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost 106:779–786

    Article  CAS  PubMed  Google Scholar 

  128. Hermansson A, Ketelhuth DF, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, Paulsson-Berne G, Hansson GK (2010) Inhibition of t cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 207:1081–1093

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK (1995) T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA 92:3893–3897

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Shah PK, Chyu KY, Dimayuga PC, Nilsson J (2014) Vaccine for atherosclerosis. J Am Coll Cardiol 64:2779–2791

    Article  CAS  PubMed  Google Scholar 

  131. Zhou X, Robertson AK, Hjerpe C, Hansson GK (2006) Adoptive transfer of cd4+ t cells reactive to modified low-density lipoprotein aggravates atherosclerosis. Arterioscler Thromb Vasc Biol 26:864–870

    Article  CAS  PubMed  Google Scholar 

  132. Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory t cells. Immunity 38:414–423

    Article  CAS  PubMed  Google Scholar 

  133. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory t cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    Article  CAS  PubMed  Google Scholar 

  134. Foks AC, Lichtman AH, Kuiper J (2015) Treating atherosclerosis with regulatory t cells. Arterioscler Thromb Vasc Biol 35:280–287

    Article  CAS  PubMed  Google Scholar 

  135. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory t cell development by the transcription factor foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  136. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85:e17–e24

    Article  CAS  PubMed  Google Scholar 

  137. Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK (2003) Disruption of tgf-beta signaling in t cells accelerates atherosclerosis. J Clin Invest 112:1342–1350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Mallat Z, Gojova A, Brun V, Esposito B, Fournier N, Cottrez F, Tedgui A, Groux H (2003) Induction of a regulatory t cell type 1 response reduces the development of atherosclerosis in apolipoprotein e-knockout mice. Circulation 108:1232–1237

    Article  CAS  PubMed  Google Scholar 

  139. Ait-Oufella H, Salomon BL, Potteaux S et al (2006) Natural regulatory t cells control the development of atherosclerosis in mice. Nat Med 12:178–180

    Article  CAS  PubMed  Google Scholar 

  140. Klingenberg R, Gerdes N, Badeau RM et al (2013) Depletion of foxp3+ regulatory t cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest 123:1323–1334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Dinh TN, Kyaw TS, Kanellakis P, To K, Tipping P, Toh BH, Bobik A, Agrotis A (2012) 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 126:1256–1266

    Article  CAS  PubMed  Google Scholar 

  142. Wigren M, Kolbus D, Duner P, Ljungcrantz I, Soderberg I, Bjorkbacka H, Fredrikson GN, Nilsson J (2011) Evidence for a role of regulatory t cells in mediating the atheroprotective effect of apolipoprotein b peptide vaccine. J Intern Med 269:546–556

    Article  CAS  PubMed  Google Scholar 

  143. Herbin O, Ait-Oufella H, Yu W, Fredrikson GN, Aubier B, Perez N, Barateau V, Nilsson J, Tedgui A, Mallat Z (2012) Regulatory t-cell response to apolipoprotein b100-derived peptides reduces the development and progression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32:605–612

    Article  CAS  PubMed  Google Scholar 

  144. Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annu Rev Immunol 30:1–22

    Article  CAS  PubMed  Google Scholar 

  145. Ait-Oufella H, Sage AP, Mallat Z, Tedgui A (2014) Adaptive (t and b cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 114:1640–1660

    Article  CAS  PubMed  Google Scholar 

  146. Zernecke A (2015) Dendritic cells in atherosclerosis: evidence in mice and humans. Arterioscler Thromb Vasc Biol 35:763–770

    Article  CAS  PubMed  Google Scholar 

  147. Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, Bozzacco L, Trumpfheller C, Park CG, Steinman RM (2009) Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med 206:497–505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Bobryshev YV, Lord RS (1995) Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of vascular dendritic cells in athero-resistant and athero-prone areas of the normal aorta. Arch Histol Cytol 58:307–322

    Article  CAS  PubMed  Google Scholar 

  149. Koltsova EK, Ley K (2011) How dendritic cells shape atherosclerosis. Trends Immunol 32:540–547

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Ley K (2014) The second touch hypothesis: T cell activation, homing and polarization. F1000Research 3:37

    PubMed Central  PubMed  Google Scholar 

  151. Lievens D, Habets KL, Robertson AK et al (2013) Abrogated transforming growth factor beta receptor ii (tgfbetarii) signalling in dendritic cells promotes immune reactivity of t cells resulting in enhanced atherosclerosis. Eur Heart J 34:3717–3727

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. Choi JH, Cheong C, Dandamudi DB, Park CG, Rodriguez A, Mehandru S, Velinzon K, Jung IH, Yoo JY, Oh GT, Steinman RM (2011) Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity 35:819–831

    Article  CAS  PubMed  Google Scholar 

  153. Subramanian M, Thorp E, Hansson GK, Tabas I (2013) Treg-mediated suppression of atherosclerosis requires myd88 signaling in dcs. J Clin Invest 123:179–188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Hermansson A, Johansson DK, Ketelhuth DF, Andersson J, Zhou X, Hansson GK (2011) Immunotherapy with tolerogenic apolipoprotein b-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 123:1083–1091

    Article  CAS  PubMed  Google Scholar 

  155. Habets KL, van Puijvelde GH, van Duivenvoorde LM, van Wanrooij EJ, de Vos P, Tervaert JW, van Berkel TJ, Toes RE, Kuiper J (2010) Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in ldl receptor-deficient mice. Cardiovasc Res 85:622–630

    Article  CAS  PubMed  Google Scholar 

  156. Sage AP, Murphy D, Maffia P et al (2014) Mhc class ii-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic t cell immunity. Circulation 130:1363–1373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI (2010) Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res 106:383–390

    Article  CAS  PubMed  Google Scholar 

  158. Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, Kreisel D, Swartz MA, Sorci-Thomas MG, Randolph GJ (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123:1571–1579

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Karvonen J, Paivansalo M, Kesaniemi YA, Horkko S (2003) Immunoglobulin m type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation 108:2107–2112

    Article  CAS  PubMed  Google Scholar 

  160. Tsimikas S, Brilakis ES, Lennon RJ, Miller ER, Witztum JL, McConnell JP, Kornman KS, Berger PB (2007) Relationship of igg and igm autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res 48:425–433

    Article  CAS  PubMed  Google Scholar 

  161. Hulthe J, Bokemark L, Fagerberg B (2001) Antibodies to oxidized ldl in relation to intima-media thickness in carotid and femoral arteries in 58-year-old subjectively clinically healthy men. Arterioscler Thromb Vasc Biol 21:101–107

    Article  CAS  PubMed  Google Scholar 

  162. Dotevall A, Hulthe J, Rosengren A, Wiklund O, Wilhelmsen L (2001) Autoantibodies against oxidized low-density lipoprotein and c-reactive protein are associated with diabetes and myocardial infarction in women. Clin Sci (Lond) 101:523–531

    Article  CAS  Google Scholar 

  163. Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, Woelkers D, Shaw PX, Choi J, Perkmann T, Backhed F, Miller YI, Horkko S, Corr M, Witztum JL, Binder CJ (2009) Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 119:1335–1349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Binder CJ, Horkko S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between streptococcus pneumoniae and oxidized ldl. Nat Med 9:736–743

    Article  CAS  PubMed  Google Scholar 

  165. Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO (2009) Immunoglobulin m is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 120:417–426

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  166. Cesena FH, Dimayuga PC, Yano J, Zhao X, Kirzner J, Zhou J, Chan LF, Lio WM, Cercek B, Shah PK, Chyu KY (2012) Immune-modulation by polyclonal igm treatment reduces atherosclerosis in hypercholesterolemic apoe-/- mice. Atherosclerosis 220:59–65

    Article  CAS  PubMed  Google Scholar 

  167. Gillotte-Taylor K, Boullier A, Witztum JL, Steinberg D, Quehenberger O (2001) Scavenger receptor class b type i as a receptor for oxidized low density lipoprotein. J Lipid Res 42:1474–1482

    CAS  PubMed  Google Scholar 

  168. Horkko S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, Berliner JA, Friedman P, Dennis EA, Curtiss LK, Palinski W, Witztum JL (1999) Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest 103:117–128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  169. Tsimikas S, Palinski W, Witztum JL (2001) Circulating autoantibodies to oxidized ldl correlate with arterial accumulation and depletion of oxidized ldl in ldl receptor-deficient mice. Arterioscler Thromb Vasc Biol 21:95–100

    Article  CAS  PubMed  Google Scholar 

  170. Yla-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL (1994) Rabbit and human atherosclerotic lesions contain igg that recognizes epitopes of oxidized ldl arteriosclerosis and thrombosis: J Vasc Biol Am Heart Assoc 14:32–40

    CAS  Google Scholar 

  171. Ravandi A, Boekholdt SM, Mallat Z, Talmud PJ, Kastelein JJ, Wareham NJ, Miller ER, Benessiano J, Tedgui A, Witztum JL, Khaw KT, Tsimikas S (2011) Relationship of igg and igm autoantibodies and immune complexes to oxidized ldl with markers of oxidation and inflammation and cardiovascular events: results from the epic-norfolk study. J Lipid Res 52:1829–1836

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  172. Tsimikas S, Miyanohara A, Hartvigsen K et al (2011) Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression. J Am Coll Cardiol 58:1715–1727

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Sjogren P, Fredrikson GN, Samnegard A, Ericsson CG, Ohrvik J, Fisher RM, Nilsson J, Hamsten A (2008) High plasma concentrations of autoantibodies against native peptide 210 of apob-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction. Eur Heart J 29:2218–2226

    Article  PubMed  CAS  Google Scholar 

  174. Palinski W, Miller E, Witztum JL (1995) Immunization of low density lipoprotein (ldl) receptor-deficient rabbits with homologous malondialdehyde-modified ldl reduces atherogenesis. Proc Natl Acad Sci USA 92:821–825

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  175. Freigang S, Horkko S, Miller E, Witztum JL, Palinski W (1998) Immunization of ldl receptor-deficient mice with homologous malondialdehyde-modified and native ldl reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol 18:1972–1982

    Article  CAS  PubMed  Google Scholar 

  176. Zhu L, He Z, Wu F, Ding R, Jiang Q, Zhang J, Fan M, Wang X, Eva B, Jan N, Liang C, Wu Z (2014) Immunization with advanced glycation end products modified low density lipoprotein inhibits atherosclerosis progression in diabetic apoe and ldlr null mice. Cardiovasc Diabetol 13:151

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  177. Fredrikson GN, Bjorkbacka H, Soderberg I, Ljungcrantz I, Nilsson J (2008) Treatment with apo b peptide vaccines inhibits atherosclerosis in human apo b-100 transgenic mice without inducing an increase in peptide-specific antibodies. J Intern Med 264:563–570

    Article  CAS  PubMed  Google Scholar 

  178. Fredrikson GN, Soderberg I, Lindholm M, Dimayuga P, Chyu KY, Shah PK, Nilsson J (2003) Inhibition of atherosclerosis in apoe-null mice by immunization with apob-100 peptide sequences. Arterioscler Thromb Vasc Biol 23:879–884

    Article  CAS  PubMed  Google Scholar 

  179. Honjo T, Chyu KY, Dimayuga PC, Yano J, Lio WM, Trinidad P, Zhao X, Zhou J, Chen S, Cercek B, Arditi M, Shah PK (2015) Apob-100-related peptide vaccine protects against angiotensin ii-induced aortic aneurysm formation and rupture. J Am Coll Cardiol 65:546–556

    Article  CAS  PubMed  Google Scholar 

  180. Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, Ketelhuth DF, Gerdes N, Holmgren J, Nilsson J, Hansson GK (2010) Intranasal immunization with an apolipoprotein b-100 fusion protein induces antigen-specific regulatory t cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 30:946–952

    Article  CAS  PubMed  Google Scholar 

  181. Chyu KY, Zhao X, Dimayuga PC, Zhou J, Li X, Yano J, Lio WM, Chan LF, Kirzner J, Trinidad P, Cercek B, Shah PK (2012) Cd8+ t cells mediate the athero-protective effect of immunization with an apob-100 peptide. PLoS ONE 7:e30780

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  182. Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, Tse H, Ley K (2013) Atheroprotective vaccination with mhc-ii restricted peptides from apob-100. Front Immunol 4:493

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  183. Hermansson A, Ketelhuth DF, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, Paulsson-Berne G, Hansson GK (2010) Inhibition of t cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 207:1081–1093

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  184. Khallou-Laschet J, Tupin E, Caligiuri G, Poirier B, Thieblemont N, Gaston AT, Vandaele M, Bleton J, Tchapla A, Kaveri SV, Rudling M, Nicoletti A (2006) Atheroprotective effect of adjuvants in apolipoprotein e knockout mice. Atherosclerosis 184:330–341

    Article  CAS  PubMed  Google Scholar 

  185. Gonen A, Hansen LF, Turner WW et al (2014) Atheroprotective immunization with malondialdehyde-modified ldl is hapten specific and dependent on advanced mda adducts: implications for development of an atheroprotective vaccine. J Lipid Res 55:2137–2155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Engelbertsen D, Rattik S, Knutsson A, Bjorkbacka H, Bengtsson E, Nilsson J (2014) Induction of t helper 2 responses against human apolipoprotein b100 does not affect atherosclerosis in apoe−/− mice. Cardiovasc Res 103:304–312

    Article  CAS  PubMed  Google Scholar 

  187. Clement M, Guedj K, Andreata F et al (2015) Control of the t follicular helper-germinal center b-cell axis by cd8+ regulatory t cells limits atherosclerosis and tertiary lymphoid organ development. Circulation 131:560–570

    Article  CAS  PubMed  Google Scholar 

  188. Hilgendorf I, Theurl I, Gerhardt LM et al (2014) Innate response activator b cells aggravate atherosclerosis by stimulating t helper-1 adaptive immunity. Circulation 129:1677–1687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  189. Sage AP, Tsiantoulas D, Baker L, Harrison J, Masters L, Murphy D, Loinard C, Binder CJ, Mallat Z (2012) Baff receptor deficiency reduces the development of atherosclerosis in mice—brief report. Arterioscler Thromb Vasc Biol 32:1573–1576

    Article  CAS  PubMed  Google Scholar 

  190. Zouggari Y, Ait-Oufella H, Bonnin P et al (2013) B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 19:1273–1280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  191. Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ (2014) B cells and humoral immunity in atherosclerosis. Circ Res 114:1743–1756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  192. Ridker PM, Danielson E, Fonseca FAH et al (2008) Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. 359:2195–2207

    CAS  Google Scholar 

  193. Ridker PM, Thuren T, Zalewski A, Libby P (2011) 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 162:597–605

    Article  CAS  PubMed  Google Scholar 

  194. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM (2013) Rationale and design of the cardiovascular inflammation reduction trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J 166(199–207):e115

    Google Scholar 

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  1. Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, CA, 92037, USA

    Dennis Wolf & Klaus Ley

  2. Atherogenesis Research Group, Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany

    Andreas Zirlik

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Wolf, D., Zirlik, A. & Ley, K. Beyond vascular inflammation—recent advances in understanding atherosclerosis. Cell. Mol. Life Sci. 72, 3853–3869 (2015). https://doi.org/10.1007/s00018-015-1971-6

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