Skip to main content

Advertisement

SpringerLink
Log in

Diversity of macrophage phenotypes and responses in atherosclerosis

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Libby P, Aikawa M, Schonbeck U (2000) Cholesterol and atherosclerosis. Biochem Biophys Acta 1529:299–309

    CAS  PubMed  Google Scholar 

  5. Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. 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  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, Derudas B, Mayi T, Bories G, Tailleux A, Haulon S, Zawadzki C, Jude B, Staels B (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the ppargamma and lxralpha pathways. Circ Res 108:985–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jenkins SJ, Ruckerl D, Thomas GD, Hewitson JP, Duncan S, Brombacher F, Maizels RM, Hume DA, Allen JE (2013) Il-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by csf-1. J Exp Med 210:2477–2491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  CAS  PubMed  Google Scholar 

  12. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  CAS  PubMed  Google Scholar 

  13. Waldo SW, Li Y, Buono C, Zhao B, Billings EM, Chang J, Kruth HS (2008) Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Pathol 172:1112–1126

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) Ppargamma activation primes human monocytes into alternative m2 macrophages with anti-inflammatory properties. Cell Metab 6:137–143

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, Hamers AAJ, Cochain C, Vafadarnejad E, Saliba AE, Zernecke A, Pramod AB, Ghosh AK, Anto Michel N, Hoppe N, Hilgendorf I, Zirlik A, Hedrick CC, Ley K, Wolf D (2018) Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell rna-sequencing and mass cytometry. Circ Res 122:1675–1688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H, Ley K, Wolf D, Saliba AE, Zernecke A (2018) Single-cell rna-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 122:1661–1674

    Article  CAS  PubMed  Google Scholar 

  18. Kim K, Shim D, Lee JS, Zaitsev K, Williams JW, Kim KW, Jang MY, Seok Jang H, Yun TJ, Lee SH, Yoon WK, Prat A, Seidah NG, Choi J, Lee SP, Yoon SH, Nam JW, Seong JK, Oh GT, Randolph GJ, Artyomov MN, Cheong C, Choi JH (2018) Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ Res 123:1127–1142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH (2004) Human il-23-producing type 1 macrophages promote but il-10-producing type 2 macrophages subvert immunity to (myco) bacteria. Proc Natl Acad Sci USA 101:4560–4565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Adamson S, Leitinger N (2011) Phenotypic modulation of macrophages in response to plaque lipids. Curr Opin Lipidol 22:335–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  CAS  PubMed  Google Scholar 

  22. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) Cd36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161

    Article  CAS  PubMed  Google Scholar 

  23. Stein M, Keshav S, Harris N, Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292

    Article  CAS  PubMed  Google Scholar 

  24. Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM (2014) Anti-inflammatory m2, but not pro-inflammatory m1 macrophages promote angiogenesis in vivo. Angiogenesis 17:109–118

    Article  CAS  PubMed  Google Scholar 

  25. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA (2001) Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta (1). J Exp Med 194:809–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen vi and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016–E1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH (2011) Macrophages in skin injury and repair. Immunobiology 216:753–762

    Article  PubMed  CAS  Google Scholar 

  28. Sierra-Filardi E, Vega MA, Sanchez-Mateos P, Corbi AL, Puig-Kroger A (2010) Heme oxygenase-1 expression in m-csf-polarized m2 macrophages contributes to lps-induced il-10 release. Immunobiology 215:788–795

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, Rayner K, Moore K, Garabedian M, Fisher EA (2011) Hdl promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci USA 108:7166–7171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Feig JE, Vengrenyuk Y, Reiser V, Wu C, Statnikov A, Aliferis CF, Garabedian MJ, Fisher EA, Puig O (2012) Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLoS One 7:e39790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feig JE, Shang Y, Rotllan N, Vengrenyuk Y, Wu C, Shamir R, Torra IP, Fernandez-Hernando C, Fisher EA, Garabedian MJ (2011) Statins promote the regression of atherosclerosis via activation of the ccr7-dependent emigration pathway in macrophages. PLoS One 6:e28534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chinetti-Gbaguidi G, Colin S, Staels B (2015) Macrophage subsets in atherosclerosis. Nat Rev Cardiol 12:10–17

    Article  CAS  PubMed  Google Scholar 

  34. Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN (2015) Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 184:436–445

    Article  PubMed  Google Scholar 

  35. Uyemura K, Demer LL, Castle SC, Jullien D, Berliner JA, Gately MK, Warrier RR, Pham N, Fogelman AM, Modlin RL (1996) Cross-regulatory roles of interleukin (il)-12 and il-10 in atherosclerosis. J Clin Investig 97:2130–2138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N, Dormont D, Gras G (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142:481–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, Ruhrberg C, Cantley LG (2011) Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 22:317–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lin JD, Nishi H, Poles J, Niu X, McCauley C, Rahman K, Brown EJ, Yeung ST, Vozhilla N, Weinstock A, Ramsey SA, Fisher EA, Loke P (2019) Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight 4(4):e124574

    Article  PubMed Central  Google Scholar 

  39. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, Khan NS, Wong CK, Shamailova R, Hill CA, Wang Z, Remark R, Li JR, Pina C, Faries C, Awad AJ, Moss N, Bjorkegren JLM, Kim-Schulze S, Gnjatic S, Ma’ayan A, Mocco J, Faries P, Merad M, Giannarelli C (2019) Single-cell immune landscape of human atherosclerotic plaques. Nat Med 25:1576–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R (2000) Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 157:1259–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Akishima Y, Akasaka Y, Ishikawa Y, Lijun Z, Kiguchi H, Ito K, Itabe H, Ishii T (2005) Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development. Mod Pathol 18:365–373

    Article  CAS  PubMed  Google Scholar 

  42. Hegyi L, Skepper JN, Cary NR, Mitchinson MJ (1996) Foam cell apoptosis and the development of the lipid core of human atherosclerosis. J Pathol 180:423–429

    Article  CAS  PubMed  Google Scholar 

  43. Geng YJ, Libby P (1995) Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol 147:251–266

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Libby P, Sukhova G, Lee RT, Galis ZS (1995) Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J Cardiovasc Pharmacol 25(Suppl 2):S9–S12

    Article  CAS  PubMed  Google Scholar 

  45. Ball RY, Stowers EC, Burton JH, Cary NR, Skepper JN, Mitchinson MJ (1995) Evidence that the death of macrophage foam cells contributes to the lipid core of atheroma. Atherosclerosis 114:45–54

    Article  CAS  PubMed  Google Scholar 

  46. Schaefer HE (1981) The role of macrophages in atherosclerosis. Haematol Blood Transfus 27:137–142

    CAS  PubMed  Google Scholar 

  47. Grainger DJ, Reckless J, McKilligin E (2004) Apolipoprotein e modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein e-deficient mice. J Immunol 173:6366–6375

    Article  CAS  PubMed  Google Scholar 

  48. Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ (1997) Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95:594–599

    Article  CAS  PubMed  Google Scholar 

  49. Siess W, Tigyi G (2004) Thrombogenic and atherogenic activities of lysophosphatidic acid. J Cell Biochem 92:1086–1094

    Article  CAS  PubMed  Google Scholar 

  50. 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  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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 Investig 94:2493–2503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J (2003) Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 100:4736–4741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Boyle JJ, Wilson B, Bicknell R, Harrower S, Weissberg PL, Fan TP (2000) Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J Pathol 192:234–242

    Article  CAS  PubMed  Google Scholar 

  54. Sambrano GR, Steinberg D (1995) Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc Natl Acad Sci USA 92:1396–1400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Miller YI, Viriyakosol S, Binder CJ, Feramisco JR, Kirkland TN, Witztum JL (2003) Minimally modified ldl binds to cd14, induces macrophage spreading via tlr4/md-2, and inhibits phagocytosis of apoptotic cells. J Biol Chem 278:1561–1568

    Article  CAS  PubMed  Google Scholar 

  56. Shaw PX, Horkko S, Tsimikas S, Chang MK, Palinski W, Silverman GJ, Chen PP, Witztum JL (2001) Human-derived anti-oxidized ldl autoantibody blocks uptake of oxidized ldl by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 21:1333–1339

    Article  CAS  PubMed  Google Scholar 

  57. Chang MK, Bergmark C, Laurila A, Horkko S, Han KH, Friedman P, Dennis EA, Witztum JL (1999) Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci USA 96:6353–6358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kojima Y, Volkmer JP, McKenna K, Civelek M, Lusis AJ, Miller CL, Direnzo D, Nanda V, Ye J, Connolly AJ, Schadt EE, Quertermous T, Betancur P, Maegdefessel L, Matic LP, Hedin U, Weissman IL, Leeper NJ (2016) Cd47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536:86–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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  CAS  PubMed  Google Scholar 

  60. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW (2002) Scavenger receptors class a-i/ii and cd36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 277:49982–49988

    Article  CAS  PubMed  Google Scholar 

  61. Kruth HS (2011) Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Curr Opin Lipidol 22:386–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) Nlrp3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Menu P, Pellegrin M, Aubert JF, Bouzourene K, Tardivel A, Mazzolai L, Tschopp J (2011) Atherosclerosis in apoe-deficient mice progresses independently of the nlrp3 inflammasome. Cell Death Dis 2:e137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bae YS, Lee JH, Choi SH, Kim S, Almazan F, Witztum JL, Miller YI (2009) Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of nadph oxidase 2. Circ Res 104:210–218 (221p following 218)

    Article  CAS  PubMed  Google Scholar 

  65. Huber J, Boechzelt H, Karten B, Surboeck M, Bochkov VN, Binder BR, Sattler W, Leitinger N (2002) Oxidized cholesteryl linoleates stimulate endothelial cells to bind monocytes via the extracellular signal-regulated kinase 1/2 pathway. Arterioscler Thromb Vasc Biol 22:581–586

    Article  CAS  PubMed  Google Scholar 

  66. Fang L, Harkewicz R, Hartvigsen K, Wiesner P, Choi SH, Almazan F, Pattison J, Deer E, Sayaphupha T, Dennis EA, Witztum JL, Tsimikas S, Miller YI (2010) Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation. J Biol Chem 285:32343–32351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Huang Z, Li W, Wang R, Zhang F, Chi Y, Wang D, Liu Z, Zhang Y, Matsuura E, Liu Q (2010) 7-Ketocholesteryl-9-carboxynonanoate induced nuclear factor-kappa b activation in j774a1 macrophages. Life Sci 87:651–657

    Article  CAS  PubMed  Google Scholar 

  68. Wartman WB (1938) Occulusion of the coronary arteries by hemorrhage into their walls. Am Heart J 15:459–470

    Article  Google Scholar 

  69. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349:2316–2325

    Article  CAS  PubMed  Google Scholar 

  70. Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ (1984) Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 310:175–177

    Article  CAS  PubMed  Google Scholar 

  71. Finn AV, Nakano M, Polavarapu R, Karmali V, Saeed O, Zhao X, Yazdani S, Otsuka F, Davis T, Habib A, Narula J, Kolodgie FD, Virmani R (2012) Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 59:166–177

    Article  CAS  PubMed  Google Scholar 

  72. Jain RK, Finn AV, Kolodgie FD, Gold HK, Virmani R (2007) Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat Clin Pract Cardiovasc Med 4:491–502

    Article  CAS  PubMed  Google Scholar 

  73. Nagy E, Eaton JW, Jeney V, Soares MP, Varga Z, Galajda Z, Szentmiklosi J, Mehes G, Csonka T, Smith A, Vercellotti GM, Balla G, Balla J (2010) Red cells, hemoglobin, heme, iron, and atherogenesis. Arterioscler Thromb Vasc Biol 30:1347–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409:198–201

    Article  CAS  PubMed  Google Scholar 

  75. Pulford K, Micklem K, McCarthy S, Cordell J, Jones M, Mason DY (1992) A monocyte/macrophage antigen recognized by the four antibodies ghi/61, ber-mac3, ki-m8 and sm4. Immunology 75:588–595

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Nielsen MJ, Moller HJ, Moestrup SK (2010) Hemoglobin and heme scavenger receptors. Antioxid Redox Signal 12:261–273

    Article  CAS  PubMed  Google Scholar 

  77. Boyle JJ, Johns M, Kampfer T, Nguyen AT, Game L, Schaer DJ, Mason JC, Haskard DO (2012) Activating transcription factor 1 directs mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res 110:20–33

    Article  CAS  PubMed  Google Scholar 

  78. Habib A, Polavarapu R, Karmali V, Guo L, Van Dam R, Cheng Q, Akahori H, Saeed O, Nakano M, Pachura K, Hong CC, Shin E, Kolodgie F, Virmani R, Finn AV (2015) Hepcidin-ferroportin axis controls toll-like receptor 4 dependent macrophage inflammatory responses in human atherosclerotic plaques. Atherosclerosis 241:692–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, Landis RC (2004) Hemoglobin scavenger receptor cd163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res 94:119–126

    Article  CAS  PubMed  Google Scholar 

  80. Landis RC, Philippidis P, Domin J, Boyle JJ, Haskard DO (2013) Haptoglobin genotype-dependent anti-inflammatory signaling in cd163(+) macrophages. Int J Inflamm 2013:980327

    Google Scholar 

  81. Boyle JJ, Harrington HA, Piper E, Elderfield K, Stark J, Landis RC, Haskard DO (2009) Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 174:1097–1108

    Article  PubMed  PubMed Central  Google Scholar 

  82. Guo L, Akahori H, Harari E, Smith SL, Polavarapu R, Karmali V, Otsuka F, Gannon RL, Braumann RE, Dickinson MH, Gupta A, Jenkins AL, Lipinski MJ, Kim J, Chhour P, de Vries PS, Jinnouchi H, Kutys R, Mori H, Kutyna MD, Torii S, Sakamoto A, Choi CU, Cheng Q, Grove ML, Sawan MA, Zhang Y, Cao Y, Kolodgie FD, Cormode DP, Arking DE, Boerwinkle E, Morrison AC, Erdmann J, Sotoodehnia N, Virmani R, Finn AV (2018) Cd163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis. J Clin Investig 128:1106–1124

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) Hifalpha targeted for vhl-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468

    Article  CAS  PubMed  Google Scholar 

  84. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, Bruick RK, Philpott CC (2011) Activation of the hif prolyl hydroxylase by the iron chaperones pcbp1 and pcbp2. Cell Metab 14:647–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J (2003) Hif prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of hif-1alpha in normoxia. EMBO J 22:4082–4090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sluimer JC, Gasc JM, van Wanroij JL, Kisters N, Groeneweg M, Sollewijn Gelpke MD, Cleutjens JP, van den Akker LH, Corvol P, Wouters BG, Daemen MJ, Bijnens AP (2008) Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 51:1258–1265

    Article  CAS  PubMed  Google Scholar 

  87. Sun J, Underhill HR, Hippe DS, Xue Y, Yuan C, Hatsukami TS (2012) Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: a long-term time course study. JACC Cardiovasc Imaging 5:798–804

    Article  PubMed  PubMed Central  Google Scholar 

  88. 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 

  89. Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, Takigami M, Kondo T, Atsumi T (2013) The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis 22:910–918

    Article  PubMed  Google Scholar 

  90. Shaikh S, Brittenden J, Lahiri R, Brown PA, Thies F, Wilson HM (2012) Macrophage subtypes in symptomatic carotid artery and femoral artery plaques. Eur J Vasc Endovasc Surg 44:491–497

    Article  CAS  PubMed  Google Scholar 

  91. Barlis P, Serruys PW, Devries A, Regar E (2008) Optical coherence tomography assessment of vulnerable plaque rupture: predilection for the plaque ‘shoulder’. Eur Heart J 29:2023

    Article  PubMed  Google Scholar 

  92. Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, Dussiot M, Levillain O, Graff-Dubois S, Nicoletti A, Caligiuri G (2010) Macrophage plasticity in experimental atherosclerosis. PLoS One 5:e8852

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Hirata Y, Kurobe H, Akaike M, Chikugo F, Hori T, Bando Y, Nishio C, Higashida M, Nakaya Y, Kitagawa T, Sata M (2011) Enhanced inflammation in epicardial fat in patients with coronary artery disease. Int Heart J 52:139–142

    Article  CAS  PubMed  Google Scholar 

  94. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M (2011) Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 58:248–255

    Article  CAS  PubMed  Google Scholar 

  95. Lee CW, Hwang I, Park CS, Lee H, Park DW, Kang SJ, Lee SW, Kim YH, Park SW, Park SJ (2013) Macrophage heterogeneity of culprit coronary plaques in patients with acute myocardial infarction or stable angina. Am J Clin Pathol 139:317–322

    Article  CAS  PubMed  Google Scholar 

  96. Wissler RW, Vesselinovitch D (1976) Studies of regression of advanced atherosclerosis in experimental animals and man. Ann N Y Acad Sci 275:363–378

    Article  CAS  PubMed  Google Scholar 

  97. Armstrong ML (1976) Evidence of regression of atherosclerosis in primates and man. Postgrad Med J 52:456–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Reis ED, Li J, Fayad ZA, Rong JX, Hansoty D, Aguinaldo JG, Fallon JT, Fisher EA (2001) Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein e-deficient mouse in a novel transplantation model. J Vasc Surg 34:541–547

    Article  CAS  PubMed  Google Scholar 

  99. Trogan E, Fayad ZA, Itskovich VV, Aguinaldo JG, Mani V, Fallon JT, Chereshnev I, Fisher EA (2004) Serial studies of mouse atherosclerosis by in vivo magnetic resonance imaging detect lesion regression after correction of dyslipidemia. Arterioscler Thromb Vasc Biol 24:1714–1719

    Article  CAS  PubMed  Google Scholar 

  100. Rahman K, Vengrenyuk Y, Ramsey SA, Vila NR, Girgis NM, Liu J, Gusarova V, Gromada J, Weinstock A, Moore KJ, Loke P, Fisher EA (2017) Inflammatory ly6chi monocytes and their conversion to m2 macrophages drive atherosclerosis regression. J Clin Investig 127:2904–2915

    Article  PubMed  PubMed Central  Google Scholar 

  101. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM (2006) Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the asteroid trial. JAMA 295:1556–1565

    Article  CAS  PubMed  Google Scholar 

  102. 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. N Engl J Med 365:2078–2087

    Article  CAS  PubMed  Google Scholar 

  103. Puri R, Nicholls SJ, Shao M, Kataoka Y, Uno K, Kapadia SR, Tuzcu EM, Nissen SE (2015) Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol 65:1273–1282

    Article  CAS  PubMed  Google Scholar 

  104. Raber L, Taniwaki M, Zaugg S, Kelbaek H, Roffi M, Holmvang L, Noble S, Pedrazzini G, Moschovitis A, Luscher TF, Matter CM, Serruys PW, Juni P, Garcia-Garcia HM, Windecker S (2015) Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (ibis-4): a serial intravascular ultrasonography study. Eur Heart J 36:490–500

    Article  PubMed  Google Scholar 

  105. Banach M, Serban C, Sahebkar A, Mikhailidis DP, Ursoniu S, Ray KK, Rysz J, Toth PP, Muntner P, Mosteoru S, Garcia-Garcia HM, Hovingh GK, Kastelein JJ, Serruys PW (2015) Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies. BMC Med 13:229

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CVPath Institute, 19 Firstfield Road, Gaithersburg, MD, 20878, USA

    Hiroyuki Jinnouchi, Liang Guo, Atsushi Sakamoto, Sho Torii, Yu Sato, Anne Cornelissen, Salome Kuntz, Ka Hyun Paek, Raquel Fernandez, Daniela Fuller, Neel Gadhoke, Dipti Surve, Maria Romero, Frank D. Kolodgie, Renu Virmani & Aloke V. Finn

Authors
  1. Hiroyuki Jinnouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsushi Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sho Torii
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anne Cornelissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salome Kuntz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ka Hyun Paek
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Raquel Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniela Fuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Neel Gadhoke
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dipti Surve
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Frank D. Kolodgie
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Renu Virmani
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Aloke V. Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aloke V. Finn.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jinnouchi, H., Guo, L., Sakamoto, A. et al. Diversity of macrophage phenotypes and responses in atherosclerosis. Cell. Mol. Life Sci. 77, 1919–1932 (2020). https://doi.org/10.1007/s00018-019-03371-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03371-3

Keywords

Search

Navigation