Hamostaseologie 2015; 35(02): 105-112
DOI: 10.5482/HAMO-14-08-0030
Review
Schattauer GmbH

Monocyte subsets in atherosclerosis

Monozyten-Subpopulationen bei Atherosklerose
M. Hristov
1   Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten (IPEK), Ludwig-Maximilians-Universität, München, Germany
,
G. H. Heine
2   Klinik für Innere Medizin IV, Universitätsklinikum des Saarlandes, Homburg, Germany
› Author Affiliations
We thank Adam Zawada and Kyrill Rogacev for comments and critical reading of the manuscript. M.H. is supported by the Deutsche Forschungsgemeinschaft (SFB 1123). Part of the work performed by G.H.H. was supported by a grant from the Else Kröner-Fresenius-Stiftung.
Further Information

Publication History

received: 14 August 2014

accepted in revised form: 29 October 2014

Publication Date:
28 December 2017 (online)

Summary

Endothelial dysfunction and chronic inflammation of the arterial wall continuously drive the development of atherosclerotic lesions. Monocytes, as cells of the innate immunity, are particularly involved in this process. In the last decade, heterogeneity of circulating monocytes has widely been acknowledged, and a recent consensus nomenclature subdivides classical, intermediate and nonclassical monocytes. Accumulating experimental and clinical data suggest a differential, subsetspecific contribution of monocytes to the pathology of atherosclerosis.

This review summarizes recent key findings on human and mouse monocyte subpopulations, specifically highlighting their phenotype, functional characteristics and mechanisms of recruitment at homeostatic conditions, in atherosclerotic vascular disease, and after acute myocardial infarction.

Zusammenfassung

Endotheliale Dysfunktion und chronische Entzündung der Gefäßwand treiben die Entwicklung atherosklerotischer Läsionen kontinuierlich voran. Als Zellen der angeborenen Immunität sind Monozyten in zentraler Weise in diesen Prozess involviert. Im vergangenen Jahrzehnt erlangte die Heterogenität der Monozyten zunehmende Beachtung, wobei eine rezente Konsensus-Nomenklatur klassische, intermediäre und nicht-klassische Monozyten differenziert. Zahlreiche experimentelle und klinische Daten deuten darauf hin, dass Monozytensubpopulationen auf spezifische Weise zur Pathogenese der Atherosklerose beitragen.

Diese Übersichtsarbeit soll zentrale Ergebnisse kürzlich publizierter Studien über humane und murine Monozytensubpopulationen zusammenfassen. Sie fokussiert auf die phänotypischen und funktionellen Charakteristika von Monozytensubpopulationen und auf Mechanismen der Rekrutierung unter homöostatischen Bedingungen, bei atherosklerotischen Gefäßerkrankungen sowie nach akutem Myokardinfarkt.

 
  • References

  • 1 Van der Laan AM, Ter ENHorst, Delewi R. et al. Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir. Eur Heart J 2014; 35: 376-385.
  • 2 Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669-692.
  • 3 Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci USA 2003; 100: 2426-2431.
  • 4 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
  • 5 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
  • 6 Ziegler-Heitbrock L, Ancuta P, Crowe S. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116: e74-e80.
  • 7 Ingersoll MA, Spanbroek R, Lottaz C. et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 2010; 115: e10-e19.
  • 8 Wong KL, Tai JJ, Wong WC. et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 2011; 118: e16-e31.
  • 9 Shantsila E, Wrigley B, Tapp L. et al. Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology. J Thromb Haemost 2011; 09: 1056-1066.
  • 10 Zawada AM, Rogacev KS, Rotter B. et al. Super- SAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 2011; 118: e50-e61.
  • 11 Cros J, Cagnard N, Woollard K. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33: 375-386.
  • 12 Mosig S, Rennert K, Krause S. et al. Different functions of monocyte subsets in familial hypercholesterolemia: potential function of CD14+CD16+ monocytes in detoxification of oxidized LDL. FASEB J 2009; 23: 866-874.
  • 13 Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71-82.
  • 14 Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 2008; 08: 802-815.
  • 15 An G, Wang H, Tang R. et al. P-selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to sites of atherosclerosis in mice. Circulation 2008; 117: 3227-3237.
  • 16 Nahrendorf M, Swirski FK, Aikawa E. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204: 3037-3047.
  • 17 Carlin LM, Stamatiades EG, Auffray C. et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 2013; 153: 362-375.
  • 18 Murphy AJ, Akhtari M, Tolani S. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 2011; 121: 4138-4149.
  • 19 Bidzhekov K, Gan L, Denecke B. et al. microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thromb Haemost 2012; 107: 619-625.
  • 20 Swirski FK, Libby P, Aikawa E. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
  • 21 Potteaux S, Gautier EL, Hutchison SB. et al. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/mice during disease regression. J Clin Invest 2011; 121: 2025-2036.
  • 22 Soehnlein O, Drechsler M, Döring Y. et al. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol Med 2013; 05: 471-481.
  • 23 Combadière C, Potteaux S, Rodero M. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008; 117: 1649-1657.
  • 24 Tacke F, Alvarez D, Kaplan TJ. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117: 185-194.
  • 25 Auffray C, Fogg D, Garfa M. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007; 317: 666-670.
  • 26 Landsman L, Bar-On L, Zernecke A. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 2009; 113: 963-972.
  • 27 Braunersreuther V, Zernecke A, Arnaud C. et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 373-379.
  • 28 Saederup N, Chan L, Lira SA. et al. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/mice: evidence for independent chemokine functions in atherogenesis. Circulation 2008; 117: 1642-1648.
  • 29 Boring L, Gosling J, Cleary M. et al. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894-897.
  • 30 Veillard NR, Kwak B, Pelli G. et al. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res 2004; 94: 253-261.
  • 31 Hilgendorf I, Gerhardt LM, Tan TC. et al. Ly6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 2014; 114: 1611-1622.
  • 32 Dutta P, Courties G, Wei Y. et al. Myocardial infarction accelerates atherosclerosis. Nature 2012; 487: 325-329.
  • 33 Gottumukkala RV, Lv H, Cornivelli L. et al. Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci Transl Med 2012; 04: 138ra80.
  • 34 Madjid M, Awan I, Willerson JT. et al. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol 2004; 44: 1945-1956.
  • 35 Hristov M, Schmitz S, Nauwelaers F, Weber C. A flow cytometric protocol for enumeration of endothelial progenitor cells and monocyte subsets in human blood. J Immunol Methods 2012; 381: 9-13.
  • 36 Heimbeck I, Hofer TP, Eder C. et al. Standardized single-platform assay for human monocyte subpopulations: Lower CD14+CD16++ monocytes in females. Cytometry A 2010; 77: 823-830.
  • 37 Rogacev KS, Ulrich C, Blömer L. et al. Monocyte heterogeneity in obesity and subclinical atherosclerosis. Eur Heart J 2010; 31: 369-376.
  • 38 Shantsila E, Tapp LD, Wrigley BJ. et al. The effects of exercise and diurnal variation on monocyte subsets and monocyte-platelet aggregates. Eur J Clin Invest 2012; 42: 832-839.
  • 39 Hristov M, Leyendecker T, Schuhmann C. et al. Circulating monocyte subsets and cardiovascular risk factors in coronary artery disease. Thromb Haemost 2010; 104: 412-414.
  • 40 Cottam DR, Schaefer PA, Shaftan GW. et al. Effect of surgically-induced weight loss on leukocyte indicators of chronic inflammation in morbid obesity. Obes Surg 2002; 12: 335-342.
  • 41 Poitou C, Dalmas E, Renovato M. et al. CD14dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31: 2322-2330.
  • 42 Rogacev KS, Cremers B, Zawada AM. et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60: 1512-1520.
  • 43 Sarnak MJ, Levey AS, Schoolwerth AC. et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108: 2154-2169.
  • 44 Nockher WA, Scherberich JE. Expanded CD14+ CD16+ monocyte subpopulation in patients with acute and chronic infections undergoing hemodialysis. Infect Immun 1998; 66: 2782-2790.
  • 45 Heine GH, Ortiz A, Massy ZA. et al. Monocyte subpopulations and cardiovascular risk in chronic kidney disease. Nat Rev Nephrol 2012; 08: 362-369.
  • 46 Timmerman KL, Flynn MG, Coen PM. et al. Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise?. J Leukoc Biol 2008; 84: 1271-1278.
  • 47 Coen PM, Flynn MG, Markofski MM. et al. Adding exercise to rosuvastatin treatment: influence on C-reactive protein, monocyte toll-like receptor 4 expression, and inflammatory monocyte (CD14+CD16+) population. Metabolism 2010; 59: 1775-1783.
  • 48 Heine GH, Ulrich C, Seibert E. et al. CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients. Kidney Int 2008; 73: 622-629.
  • 49 Rogacev KS, Ziegelin M, Ulrich C. et al. Haemodialysis-induced transient CD16+ monocytopenia and cardiovascular outcome. Nephrol Dial Transplant 2009; 24: 3480-3486.
  • 50 Ulrich C, Heine GH, Seibert E. et al. Circulating monocyte subpopulations with high expression of angiotensin-converting enzyme predict mortality in patients with end-stage renal disease. Nephrol Dial Transplant 2010; 25: 2265-2272.
  • 51 Rogacev KS, Seiler S, Zawada AM. et al. CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 2011; 32: 84-92.
  • 52 Rogacev KS, Zawada AM, Emrich I. et al. Lower Apo A-I and lower HDL-C levels are associated with higher intermediate CD14++CD16+ monocyte counts that predict cardiovascular events in CKD. Arterioscler Thromb Vasc Biol 2014; 34: 2120-2127.
  • 53 Berg KE, Ljungcrantz I, Andersson L. et al. Elevated CD14++CD16– monocytes predict cardiovascular events. Circ Cardiovasc Genet 2012; 05: 122-131.
  • 54 Mehta NN, Reilly MP. Monocyte mayhem: do subtypes modulate distinct atherosclerosis phenotypes?. Circ Cardiovasc Genet 2012; 05: 7-9.
  • 55 Rogacev KS, Zawada AM, Hundsdorfer J. et al. Immunosuppression and monocyte subsets. Nephrol Dial Transplant. 2014 in press.
  • 56 Zhao Q. Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. J Leukoc Biol 2010; 88: 41-55.
  • 57 Tsujioka H, Imanishi T, Ikejima H. et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol 2009; 54: 130-138.
  • 58 Tapp LD, Shantsila E, Wrigley BJ. et al. The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. J Thromb Haemost 2012; 10: 1231-1241.
  • 59 Leers MP, Keuren JF, Frissen ME. et al. The proand anticoagulant role of blood-borne phagocytes in patients with acute coronary syndrome. Thromb Haemost 2013; 110: 101-109.
  • 60 Von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
  • 61 Theilmeier G, Lenaerts T, Remacle C. et al. Circulating activated platelets assist THP-1 monocytoid/endothelial cell interaction under shear stress. Blood 1999; 94: 2725-2734.
  • 62 Keating FK, Dauerman HL, Whitaker DA. et al. Increased expression of platelet P-selectin and formation of platelet-leukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thromb Res 2006; 118: 361-369.
  • 63 Shantsila E, Lip GY. The role of monocytes in thrombotic disorders. Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thromb Haemost 2009; 102: 916-924.
  • 64 Freeburn JC, Wallace JM, Strain JJ. et al. Monocyte tissue factor-like activity in post myocardial infarction patients. Br J Haematol 1998; 102: 605-608.