1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Mechanisms of Myeloid Cell Modulation of Atherosclerosis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Buy this Microbiology Spectrum Article
Price Non-Member $15.00
  • Authors: Filip K. Swirski1, Matthias Nahrendorf2, Peter Libby3
  • Editor: Siamon Gordon4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; 2: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; 3: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; 4: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0026-2015
  • Received 27 October 2015 Accepted 21 January 2016 Published 19 August 2016
  • Peter Libby, plibby@bwh.harvard.edu
image of Mechanisms of Myeloid Cell Modulation of Atherosclerosis
    Preview this microbiology spectrum article:
    Zoom in
    Zoomout

    Mechanisms of Myeloid Cell Modulation of Atherosclerosis, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/4/4/MCHD-0026-2015-1.gif /docserver/preview/fulltext/microbiolspec/4/4/MCHD-0026-2015-2.gif
  • Abstract:

    Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial wall, endothelium, and smooth muscle and promote the disease and its complications. Myeloid cells participate critically in all phases of atherosclerosis from initiation through progression, and ultimately the thrombotic consequences of this disease. Foam cells, lipid-laden macrophages, constitute the hallmark of atheromata. Much of the recent expansion in knowledge of the roles of myeloid cells in atherosclerosis revolves around the functional contributions of subsets of monocytes, precursors of macrophages, the most abundant myeloid cells in the atheroma. Proinflammatory monocytes preferentially accumulate in nascent atherosclerotic plaques. The most dramatic manifestations of atherosclerosis result from blood clot formation. Myocardial infarction, ischemic stroke, and abrupt limb ischemia all arise primarily from thrombi that complicate atherosclerotic plaques. Myeloid cells contribute pivotally to triggering thrombosis, for example, by elaborating enzymes that degrade the plaque’s protective extracellular matrix, rendering it fragile, and by producing the potent procoagulant tissue factor. While most attention has focused on mononuclear phagocytes, the participation of polymorphonuclear leukocytes may aggravate local thrombus formation. Existing therapies such as statins may exert some of their protective effects by altering the functions of myeloid cells. The pathways of innate immunity that involve myeloid cells provide a myriad of potential targets for modifying atherosclerosis and its complications, and provide a fertile field for future attempts to address the residual burden of this disease, whose global prevalence is on the rise.

  • Citation: Swirski F, Nahrendorf M, Libby P. 2016. Mechanisms of Myeloid Cell Modulation of Atherosclerosis. Microbiol Spectrum 4(4):MCHD-0026-2015. doi:10.1128/microbiolspec.MCHD-0026-2015.

Key Concept Ranking

Transforming Growth Factor beta
0.44244614
0.44244614

References

1. Osler W. 1892. The Principles and Practice of Medicine. D. Appleton and Company, New York, NY.
2. Rokitansky K. 1855. A Manual of Pathological Anatomy, vol IV, p 201–208. Blanchard and Lea, Philadelphia, PA.
3. Virchow R. 1858. Cellular Pathology. John Churchill, London, United Kingdom.
4. Benditt EP, Benditt JM. 1973. Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci U S A 70:1753–1756. [PubMed][CrossRef]
5. Ross R, Glomset JA. 1973. Atherosclerosis and the arterial smooth muscle cells. Science 180:1332–1339. [PubMed][CrossRef]
6. Ross R, Glomset J, Kariya B, Harker L. 1974. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A 71:1207–1210. [PubMed][CrossRef]
7. Anitschkow N, Chalatow S. 1983. On experimental cholesterin steatosis and its significance in the origin of some pathological processes (1913). Arteriosclerosis 3:178–182. [PubMed][CrossRef]
8. Steinberg D. 2013. In celebration of the 100th anniversary of the lipid hypothesis of atherosclerosis. J Lipid Res 54:2946–2949. [PubMed][CrossRef]
9. Ross R, Harker L. 1976. Hyperlipidemia and atherosclerosis. Science 193:1094–1100. [PubMed][CrossRef]
10. Poole JC, Florey HW. 1958. Changes in the endothelium of the aorta and the behaviour of macrophages in experimental atheroma of rabbits. J Pathol Bacteriol 75:245–251. [PubMed][CrossRef]
11. Joris I, Zand T, Nunnari JJ, Krolikowski FJ, Majno G. 1983. Studies on the pathogenesis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats. Am J Pathol 113:341–358. [PubMed]
12. 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]
13. Faggiotto A, Ross R. 1984. Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque. Arteriosclerosis 4:341–356. [PubMed][CrossRef]
14. Faggiotto A, Ross R, Harker L. 1984. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 4:323–340. [PubMed][CrossRef]
15. Libby P. 1990. Inflammatory and immune mechanisms in atherogenesis, p 79–89. In Leaf A, Weber P (ed), Atheroclerosis Reviews, vol 21. Raven Press, New York, NY.
16. Hansson GK, Jonasson L. 2009. The discovery of cellular immunity in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 29:1714–1717. [PubMed][CrossRef]
17. Libby P. 2012. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 32:2045–2051. [PubMed][CrossRef]
18. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J, III. 1961. Factors of risk in the development of coronary heart disease—six year follow-up experience. The Framingham Study. Ann Intern Med 55:33–50. [PubMed][CrossRef]
19. Brown MS, Goldstein JL. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47. [PubMed][CrossRef]
20. Steinberg D. 2005. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans. J Lipid Res 46:179–190. [PubMed][CrossRef]
21. Steinberg D. 2004. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I. J Lipid Res 45:1583–1593. [PubMed][CrossRef]
22. Hansson GK, Libby P, Schönbeck U, Yan ZQ. 2002. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91:281–291. [PubMed][CrossRef]
23. Libby P, Hansson GK. 2015. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res 116:307–311. [PubMed][CrossRef]
24. Libby P. 2013. Collagenases and cracks in the plaque. J Clin Invest 123:3201–3203. [PubMed][CrossRef]
25. Lahoute C, Herbin O, Mallat Z, Tedgui A. 2011. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol 8:348–358. [PubMed][CrossRef]
26. Libby P, Ridker PM, Hansson GK. 2011. Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325. [PubMed][CrossRef]
27. Soehnlein O. 2012. Multiple roles for neutrophils in atherosclerosis. Circ Res 110:875–888. [PubMed][CrossRef]
28. Mestas J, Ley K. 2008. Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 18:228–232. [PubMed][CrossRef]
29. Munro JM, Cotran RS. 1988. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest 58:249–261. [PubMed]
30. O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD, Lobb R, Alpers C. 1993. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 92:945–951. [PubMed][CrossRef]
31. Libby P, Li H. 1993. Vascular cell adhesion molecule-1 and smooth muscle cell activation during atherogenesis. J Clin Invest 92:538–539. [PubMed][CrossRef]
32. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. [PubMed][CrossRef]
33. 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. [PubMed][CrossRef]
34. 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. [PubMed][CrossRef]
35. Woollard KJ, Geissmann F. 2010. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7:77–86. [PubMed][CrossRef]
36. Weber C, Zernecke A, Libby P. 2008. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8:802–815. [PubMed][CrossRef]
37. Saederup N, Chan L, Lira SA, Charo IF. 2008. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2–/– mice: evidence for independent chemokine functions in atherogenesis. Circulation 117:1642–1648. [PubMed][CrossRef]
38. Soehnlein O, Drechsler M, Döring Y, Lievens D, Hartwig H, Kemmerich K, Ortega-Gómez A, Mandl M, Vijayan S, Projahn D, Garlichs CD, Koenen RR, Hristov M, Lutgens E, Zernecke A, Weber C. 2013. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol Med 5:471–481. [PubMed][CrossRef]
39. 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 U S A 103:10340–10345. [PubMed][CrossRef]
40. van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, Rayner AJ, McDonald TO, O’Brien KD, Stuart LM, Fisher EA, Lacy-Hulbert A, Moore KJ. 2012. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 13:136–143. [PubMed][CrossRef]
41. Wanschel A, Seibert T, Hewing B, Ramkhelawon B, Ray TD, van Gils JM, Rayner KJ, Feig JE, O’Brien ER, Fisher EA, Moore KJ. 2013. Neuroimmune guidance cue Semaphorin 3E is expressed in atherosclerotic plaques and regulates macrophage retention. Arterioscler Thromb Vasc Biol 33:886–893. [PubMed][CrossRef]
42. Swirski FK, Nahrendorf M, Libby P. 2012. The ins and outs of inflammatory cells in atheromata. Cell Metab 15:135–136. [PubMed][CrossRef]
43. Cybulsky MI, Jongstra-Bilen J. 2010. Resident intimal dendritic cells and the initiation of atherosclerosis. Curr Opin Lipidol 21:397–403. [PubMed][CrossRef]
44. Packard RR, Maganto-García E, Gotsman I, Tabas I, Libby P, Lichtman AH. 2008. CD11c+ dendritic cells maintain antigen processing, presentation capabilities, and CD4+ T-cell priming efficacy under hypercholesterolemic conditions associated with atherosclerosis. Circ Res 103:965–973. [PubMed][CrossRef]
45. Gimbrone MA Jr, García-Cardeña G. 2013. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 22:9–15. [PubMed][CrossRef]
46. Chatzizisis YS, Blankstein R, Libby P. 2014. Inflammation goes with the flow: implications for non-invasive identification of high-risk plaque. Atherosclerosis 234:476–478. [PubMed][CrossRef]
47. Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. 2006. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 203:2073–2083. [PubMed][CrossRef]
48. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe DW, Libby P. 1992. Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol 140:301–316. [PubMed]
49. Stary HC. 1989. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 9(Suppl):I19–I32. [PubMed]
50. 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. [CrossRef]
51. Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, Gorbatov R, Sukhova GK, Gerhardt LM, Smyth D, Zavitz CC, Shikatani EA, Parsons M, van Rooijen N, Lin HY, Husain M, Libby P, Nahrendorf M, Weissleder R, Swirski FK. 2013. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166–1172. [PubMed][CrossRef]
52. Geng YJ, Libby P. 1995. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1β-converting enzyme. Am J Pathol 147:251–266. [PubMed]
53. Geng YJ, Libby P. 2002. Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 22:1370–1380. [PubMed][CrossRef]
54. Li S, Sun Y, Liang CP, Thorp EB, Han S, Jehle AW, Saraswathi V, Pridgen B, Kanter JE, Li R, Welch CL, Hasty AH, Bornfeldt KE, Breslow JL, Tabas I, Tall AR. 2009. Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet. Circ Res 105:1072–1082. [PubMed][CrossRef]
55. Thorp E, Tabas I. 2009. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol 86:1089–1095. [PubMed][CrossRef]
56. Libby P, Tabas I, Fredman G, Fisher EA. 2014. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867–1879. [PubMed][CrossRef]
57. Brogi E, Winkles JA, Underwood R, Clinton SK, Alberts GF, Libby P. 1993. Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages. J Clin Invest 92:2408–2418. [PubMed][CrossRef]
58. Sluimer JC, Daemen MJ. 2009. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 218:7–29. [PubMed][CrossRef]
59. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A. 1998. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 101:2702–2710. [PubMed][CrossRef]
60. New SE, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K, Libby P, Shanahan CM, Croce K, Aikawa E. 2013. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 113:72–77. [PubMed][CrossRef]
61. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. 2004. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol 24:1359–1366. [PubMed][CrossRef]
62. Libby P. 2013. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 368:2004–2013. [PubMed][CrossRef]
63. Bentzon JF, Otsuka F, Virmani R, Falk E. 2014. Mechanisms of plaque formation and rupture. Circ Res 114:1852–1866. [PubMed][CrossRef]
64. Ueno T, Dutta P, Keliher E, Leuschner F, Majmudar M, Marinelli B, Iwamoto Y, Figueiredo JL, Christen T, Swirski FK, Libby P, Weissleder R, Nahrendorf M. 2013. Nanoparticle PET-CT detects rejection and immunomodulation in cardiac allografts. Circ Cardiovasc Imaging 6:568–573. [PubMed][CrossRef]
65. Quillard T, Araújo HA, Franck G, Tesmenitsky Y, Libby P. 2014. Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata. Arterioscler Thromb Vasc Biol 34:1179–1186. [PubMed][CrossRef]
66. Quillard T, Araújo HA, Franck G, Shvartz E, Sukhova G, Libby P. 2015. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 36:1394–1404. [PubMed][CrossRef]
67. Megens RT, Vijayan S, Lievens D, Döring Y, van Zandvoort MA, Grommes J, Weber C, Soehnlein O. 2012. Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost 107:597–598. [PubMed][CrossRef]
68. Borissoff JI, Joosen IA, Versteylen MO, Brill A, Fuchs TA, Savchenko AS, Gallant M, Martinod K, Ten Cate H, Hofstra L, Crijns HJ, Wagner DD, Kietselaer BL. 2013. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol 33:2032–2040. [PubMed][CrossRef]
69. Stakos DA, Kambas K, Konstantinidis T, Mitroulis I, Apostolidou E, Arelaki S, Tsironidou V, Giatromanolaki A, Skendros P, Konstantinides S, Ritis K. 2015. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 36:1405–1414. [PubMed][CrossRef]
70. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. 2015. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349:316–320. [PubMed][CrossRef]
71. Sun J, Sukhova GK, Wolters PJ, Yang M, Kitamoto S, Libby P, MacFarlane LA, Mallen-St Clair J, Shi GP. 2007. Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13:719–724. [PubMed][CrossRef]
72. Libby P, Shi GP. 2007. Mast cells as mediators and modulators of atherogenesis. Circulation 115:2471–2473. [PubMed][CrossRef]
73. Wang J, Lindholt JS, Sukhova GK, Shi MA, Xia M, Chen H, Xiang M, He A, Wang Y, Xiong N, Libby P, Wang JA, Shi GP. 2014. IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol Med 6:952–969. [PubMed][CrossRef]
74. Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, Biessen EA. 2007. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation 115:2516–2525. [PubMed][CrossRef]
75. Willems S, Vink A, Bot I, Quax PH, de Borst GJ, de Vries JP, van de Weg SM, Moll FL, Kuiper J, Kovanen PT, de Kleijn DP, Hoefer IE, Pasterkamp G. 2013. Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events. Eur Heart J 34:3699–3706. [PubMed][CrossRef]
76. Sager HB, Dutta P, Dahlman JE, Hulsmans M, Courties G, Sun Y, Heidt T, Vinegoni C, Borodovsky A, Fitzgerald K, Wojtkiewicz GR, Iwamoto Y, Tricot B, Khan OF, Kauffman KJ, Xing Y, Shaw TE, Libby P, Langer R, Weissleder R, Swirski FK, Anderson DG, Nahrendorf M. 2016. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci Transl Med 8:342ra80. [PubMed][CrossRef]
77. Courties G, Heidt T, Sebas M, Iwamoto Y, Jeon D, Truelove J, Tricot B, Wojtkiewicz G, Dutta P, Sager HB, Borodovsky A, Novobrantseva T, Klebanov B, Fitzgerald K, Anderson DG, Libby P, Swirski FK, Weissleder R, Nahrendorf M. 2014. In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol 63:1556–1566. [PubMed][CrossRef]
78. Jain MK, Ridker PM. 2005. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 4:977–987. [PubMed][CrossRef]
79. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. 2013. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 61:404–410. [PubMed][CrossRef]
80. 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.e15. doi:10.1016/j.ahj.2013.03.018. [CrossRef]
81. Ridker PM, Thuren T, Zalewski A, Libby P. 2011. Interleukin-1β 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. [PubMed][CrossRef]
82. Shah PK, Chyu KY, Dimayuga PC, Nilsson J. 2014. Vaccine for atherosclerosis. J Am Coll Cardiol 64:2779–2791. [PubMed][CrossRef]
83. Nilsson J, Lichtman A, Tedgui A. 2015. Atheroprotective immunity and cardiovascular disease: therapeutic opportunities and challenges. J Intern Med 278:507–519. [PubMed][CrossRef]
84. Libby P, Pasterkamp G. 2015. Requiem for the ‘vulnerable plaque’. Eur Heart J 36:2984–2987. [PubMed][CrossRef]
microbiolspec.MCHD-0026-2015.citations
cm/4/4
content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0026-2015
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0026-2015
2016-08-19
2017-09-24

Abstract:

Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial wall, endothelium, and smooth muscle and promote the disease and its complications. Myeloid cells participate critically in all phases of atherosclerosis from initiation through progression, and ultimately the thrombotic consequences of this disease. Foam cells, lipid-laden macrophages, constitute the hallmark of atheromata. Much of the recent expansion in knowledge of the roles of myeloid cells in atherosclerosis revolves around the functional contributions of subsets of monocytes, precursors of macrophages, the most abundant myeloid cells in the atheroma. Proinflammatory monocytes preferentially accumulate in nascent atherosclerotic plaques. The most dramatic manifestations of atherosclerosis result from blood clot formation. Myocardial infarction, ischemic stroke, and abrupt limb ischemia all arise primarily from thrombi that complicate atherosclerotic plaques. Myeloid cells contribute pivotally to triggering thrombosis, for example, by elaborating enzymes that degrade the plaque’s protective extracellular matrix, rendering it fragile, and by producing the potent procoagulant tissue factor. While most attention has focused on mononuclear phagocytes, the participation of polymorphonuclear leukocytes may aggravate local thrombus formation. Existing therapies such as statins may exert some of their protective effects by altering the functions of myeloid cells. The pathways of innate immunity that involve myeloid cells provide a myriad of potential targets for modifying atherosclerosis and its complications, and provide a fertile field for future attempts to address the residual burden of this disease, whose global prevalence is on the rise.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Roles of myeloid cells in the evolution of the atherosclerotic plaque. This figure depicts the participation of myeloid cells in the evolution of the atheroma from the inception (left) through the progression and complication of the plaque (middle to right). Dendritic cells may populate the normal arterial intima. Early in the atherogenesis, monocytes adhere to endothelial cells (left). The adherent monocytes can diapedese into the intima and mature into macrophages. These cells imbibe lipid and become foam cells, a hallmark of the atheromatous plaque. These cells populate the lipid core of the evolving atheroma (yellow central potion, middle.) These foamy macrophages can elaborate many mediators that amplify and sustain the atherogenic process. In particular, they can secrete interstitial collagenases, members of the MMP family, that can degrade the collagen fibrils that lend strength to the fibrous cap that overlies the lipid core of the established atheroma. Cleavage of collagen in the plaque’s fibrous cap allows contact of the blood coagulation components with the procoagulant tissue factor produced by the plaque macrophages. Thus, disruption of the plaque by a fracture of the fibrous cap triggers thrombosis that leads to the most dreaded clinical complications of atherosclerosis such as the acute coronary syndromes and many ischemic strokes. Macrophages can die within plaques, as shown by the cell with the pyknotic nucleus casting off apoptotic bodies that can bear tissue factor. Macrophages can also release microparticles that can provide a nidus for spotty calcification associated with plaque instability. Calcium mineral can coalesce into plates that complicate the advanced atherosclerotic plaque. As plaques mature, they can become less cellular and accumulate more extracellular matrix. In regions of plaques rich in proteoglycan and glycosaminoglycans, endothelial cells can detach, exposing blood to underlying collagen and other thrombogenic mediators that can instigate clot formation. This process, denoted superficial erosion, can lead to recruitment of polymorphonuclear leukocytes (PMNs). Dying granulocytes release DNA that can associate with the pro-oxidant enzyme myeloperoxidase, the procoagulant tissue factor, and other enzymes associated with further endothelial damage and thrombosis. These NETs can further entrap platelets, promoting propagation of thrombi. The dendritic cells in plaques can present antigen to T cells, providing a link between innate and adaptive immunity. Mast cells in the adventitia of arteries can elaborate numerous mediators including histamine, heparin, serine proteinases, and cytokines that can amplify atherogenesis and lesion complication. Thus, myeloid cells participate in all phases of atherogenesis, from lesion initiation (left) through thrombotic complications (middle and right).

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0026-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Monocyte and macrophage diversity in relation to cardiovascular homeostasis. Blood monocytes derive from hematopoiesis in the bone marrow or from extramedullary hematopoiesis in the spleen that harbors a preformed pool of proinflammatory monocytes in mice. Monocytes enter tissues in response to chemoattractants that engage the chemokine receptors CCR2, CCR5, and CX3CR1. Hematopoietic growth factors, notably CSF-1 (M-CSF), promote the maturation of monocytes into tissue macrophages. Once recruited to and resident in tissues, macrophages can polarize toward a proinflammatory set of functions including production of cytokines such as TNF or IL-1 isoforms. IRF5 provides an example of a transcription factor that promotes the polarization of macrophages toward the proinflammatory palette of functions. The transcription factor NF-κB regulates the genes that encode a number of proinflammatory mediators elaborated by the proinflammatory subset of macrophages (pink box). Monocytes/macrophages can modulate toward a reparative and resolution-promoting set of functions under the influence of various transcription factors including nuclear receptor subfamily 4 group a member 1 (NR4a1), also known as Nur77. Mediators elaborated by the reparative subset of macrophages include IL-10; vascular endothelial growth factor (VEGF), a stimulator of angiogenesis; and transforming growth factor β (TGF-β), an anti-inflammatory and fibrogenic protein. The balance between the proinflammatory versus anti-inflammatory, reparative, and resolution functions of macrophages determines critical aspects of atherogenesis and aspects of myocardial disease related to repair of ischemic injury and the responses to hemodynamic overload conditions, features of myocardial remodeling critical in determining clinical course including the development of heart failure. ROS, reactive oxygen species (e.g., superoxide anion and hypochlorous acid); RNS, reactive nitrogen species (e.g., nitric oxide).

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0026-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Distinctions between superficial erosion and fibrous cap rupture as causes of arterial thrombosis. Source: reference 84 , with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0026-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

A depiction of potential pathophysiologic pathways that yield superficial erosion and thrombosis on atherosclerotic plaques. The bottom of the diagram depicts a longitudinal section of an artery that harbors an extracellular matrix-rich atheroma. The darker brown indicates accumulation of the proteoglycans such as versican and biglycan and of the glycosaminoglycan hyaluronic acid. (1) Some possible triggers for endothelial damage that causes superficial erosion. Inciting stimuli could include pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), or other ligands for innate immune receptors, including Toll-like receptor 2 (TLR2). These ligands bind to pattern recognition receptors on the surface of the endothelial cell. Hyaluronan, a common constituent of plaques that have undergone superficial erosion, can activate TLR2. Various apoptotic stimuli elaborated by myeloid cells in plaques, as well as oxidized lipoproteins, can unleash endothelial apoptosis. Matrix-degrading enzymes including MMPs can catabolize constituents of the basement membrane that comprises a substrate for endothelial cell adherence via integrins or other adhesion molecules. The nonfibrillar collagenases MMP-2 and MMP-9 and the activator of MMP-2, MMP-14, enzymes that localize in atheromata, may cleave the tethers of the endothelial cell to the basement membrane. (2) Some of the downstream effects of erosion. Once an endothelial cell has sloughed (as portrayed by the endothelial cell with nuclear pycnosis), the moribund endothelial cell can spew forth microparticles rich in tissue factor, a potent procoagulant. Uncovering the subendothelial matrix stimulates sticking of granulocytes and their activation and degranulation. Granulocytes elaborate reactive oxygen species (ROS) such as hypochlorous acid, HOCI, produced by myeloperoxidase (MPO), as well as superoxide anion (O ). This scheme postulates arrival of granulocytes secondarily, only after the initial disturbance of the endothelial monolayer. Granulocytes can also release myeloid-related protein (MRP) 8/14, a calgranulin family member implicated in inflammation and other aspects of atherothrombosis. Agonal granulocytes release DNA and citrullinated histones that contribute to NETosis, the formation of NETs. NETs can promote propagation of thrombosis and entrap further myeloid cells and platelets that amplify regional inflammation. Exposure of the subendothelial extracellular matrix macromolecules can also activate platelets, triggering their degranulation and elaboration of proinflammatory mediators including IL-6 and RANTES. In addition, activated platelets release plasminogen activator inhibitor-1 (PAI-1), which inhibits endogenous fibrinolysis, stabilizing clots. PMN, polymorphonuclear leukocyte. Source: reference 66 , with permission.

Source: microbiolspec August 2016 vol. 4 no. 4 doi:10.1128/microbiolspec.MCHD-0026-2015
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error