Role and analysis of monocyte subsets in cardiovascular disease

Summary

Monocytes as cells of the innate immunity are prominently involved in the development of atherosclerotic lesions. The heterogeneity of blood monocytes has widely been acknowledged by accumulating experimental and clinical data suggesting a differential, subset-specific contribution of the corresponding subpopulations to the pathology of cardiovascular and other diseases. This document re-evaluates current nomenclature and summarises key findings on monocyte subset biology to propose a consensus statement about phenotype, separation and quantification of the individual subsets.

Note: The review process for this paper was fully handled by Lina Badimon, Section Editor.

Keywords

Atherosclerosis - leukocyte function / activation - monocytes

• References

• 1 Janeway Jr. CA, Medzhitov R.. Innate immune recognition. Annu Rev Immunol 2002; 20: 197-216.
• 2 Kantari C. et al. The role of neutrophils and monocytes in innate immunity. Contribut Microbiol 2008; 15: 118-146.
• 3 Zhao Y. et al. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci USA 2003; 100: 2426-2431.
• 4 Monie TP. et al. Activating immunity: lessons from the TLRs and NLRs. Trends Biochem Sci 2009; 34: 553-561.
• 5 Horne BD. et al Intermountain Heart Collaborative Study G. Which white blood cell subtypes predict increased cardiovascular risk?. J Am Coll Cardiol 2005; 45: 1638-1643.
• 6 Zalai CV. et al. Increased circulating monocyte activation in patients with unstable coronary syndromes. J Am Coll Cardiol 2001; 38: 1340-1347.
• 7 Passlick B. et al. Identification and characterisation of a novel monocyte sub-population in human peripheral blood. Blood 1989; 74: 2527-2534.
• 8 Ziegler-Heitbrock L. et al Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116: e74-80.
• 9 Shantsila E. et al. Immunophenotypic characterisation of human monocyte subsets: possible implications for cardiovascular disease pathophysiology. J Thomb Haemost 2011; 09: 1056-1066.
• 10 Van Craenenbroeck AH. et al Acute exercise-induced response of monocyte subtypes in chronic heart and renal failure. Mediat Inflamm 2014; 2014: 216-534.
• 11 Zeng S. et al. Monocyte subsets and monocyte-platelet aggregates in patients with unstable angina. J Thromb Thrombol 2014; 38: 439-446.
• 12 Rong MY. et al. Platelets induce a proinflammatory phenotype in monocytes via the CD147 pathway in rheumatoid arthritis. Arthr Res Therap 2014; 16: 478.
• 13 Al-Sharea A. et al Native LDL promotes differentiation of human monocytes to macrophages with an inflammatory phenotype. Thromb Haemost 2016; 115: 762-772.
• 14 Murray PJ. et al. Macrophage activation and polarisation: nomenclature and experimental guidelines. Immunity 2014; 41: 14-20.
• 15 Cros J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33: 375-386.
• 16 Wong KL. et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 2011; 118: e16-31.
• 17 Grage-Griebenow E. et al Identification of a novel dendritic cell-like subset of CD64(+) / CD16(+) blood monocytes. Eur J Immunol 2001; 31: 48-56.
• 18 Zawada AM. et al. SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 2011; 118: e50-61.
• 19 Skrzeczynska-Moncznik J. et al Peripheral blood CD14high CD16+ monocytes are main producers of IL-10. Scand J Immunol 2008; 67: 152-159.
• 20 Mikolajczyk TP. et al. Interaction of human peripheral blood monocytes with apoptotic polymorphonuclear cells. Immunology 2009; 128: 103-113.
• 21 Schmidl C. et al. Transcription and enhancer profiling in human monocyte subsets. Blood 2014; 123: e90-99.
• 22 Thomas G. et al. Nonclassical patrolling monocyte function in the vasculature. Arterioscl Thromb Vasc Biol 2015; 35: 1306-1316.
• 23 Saja MF. et al. Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1(low) Monocytes. Cell Rep 2015; 12: 1802-1815.
• 24 Misharin AV. et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep 2014; 09: 591-604.
• 25 Collison JL. et al. Heterogeneity in the Locomotory Behavior of Human Monocyte Subsets over Human Vascular Endothelium In Vitro. J Immunol 2015; 195: 1162-1170.
• 26 Wang ZQ. et al. Interleukin-10 induces macrophage apoptosis and expression of CD16 (FcgammaRIII) whose engagement blocks the cell death programme and facilitates differentiation. Immunology 2001; 102: 331-337.
• 27 Mandl M. et al. Characterisation of the CD14++CD16+ Monocyte Population in Human Bone Marrow. PloS one 2014; 09: e112140.
• 28 Tapp LD. 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.
• 29 Rossol M. et al. The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthr Rheuma 2012; 64: 671-677.
• 30 Rogacev KS. et al. Immunosuppression and monocyte subsets. Nephrol Dialysis Transplant 2015; 30: 143-153.
• 31 Shantsila E. et al. The effects of exercise and diurnal variation on monocyte subsets and monocyte-platelet aggregates. Eur J Clin Invest 2012; 42: 832-839.
• 32 Dimitrov S. et al. Number and function of circulating human antigen presenting cells regulated by sleep. Sleep 2007; 30: 401-411.
• 33 Steppich B. et al. Selective mobilisation of CD14(+)CD16(+) monocytes by exercise. Am J Physiol Cell Physiol 2000; 279: C578-586.
• 34 Kittner JM. et al. Adrenaline-induced immunological changes are altered in patients with rheumatoid arthritis. Rheumatology 2002; 41: 1031-1039.
• 35 Dimitrov S. et al. Selective mobilisation of cytotoxic leukocytes by epinephrine. J Immunol 2010; 184: 503-511.
• 36 Lundahl J. et al. Altered expression of CD11b/CD18 and CD62L on human monocytes after cell preparation procedures. J Immunol Methods 1995; 180: 93-100.
• 37 Gratama JW. et al. Comparison of single and dual-platform assay formats for CD34+ haematopoietic progenitor cell enumeration. Clin Lab Haematol 1999; 21: 337-346.
• 38 Hristov M. et al. A flow cytometric protocol for enumeration of endothelial progenitor cells and monocyte subsets in human blood. J Immunol Methods 2012; 381: 9-13.
• 39 Chen C. et al. Molecular cloning and expression of early T cell costimulatory molecule-1 and its characterisation as B7–2 molecule. J Immunol 1994; 152: 4929-4936.
• 40 Jeannin P. et al. Human effector memory T cells express CD86: a functional role in naive T cell priming. J Immunol 1999; 162: 2044-2048.
• 41 Rogacev KS. 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.
• 42 Rogacev KS. et al. Haemodialysis-induced transient CD16+ monocytopenia and cardiovascular outcome. Nephrol Dialysis Transplant 2009; 24: 3480-3486.
• 43 Ziegler-Heitbrock L, Hofer TP. Toward a refined definition of monocyte subsets. Front Immunol 2013; 04: 23.
• 44 Heine GH. et al. CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients. Kidney Intern 2008; 73: 622-629.
• 45 Wong KL. et al. The three human monocyte subsets: implications for health and disease. Immunol Res 2012; 53: 41-57.
• 46 Zawada AM. et al. Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study. Cytometry A 2015; 87: 750-758.
• 47 Hofer TP. et al. Characterisation of subsets of the CD16-positive monocytes: impact of granulomatous inflammation and M-CS F-receptor mutation. Blood. 2015 Epub ahead of print.
• 48 Docke WD. et al. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem 2005; 51: 2341-2347.
• 49 Hayward AR. et al. Delayed separation of the umbilical cord, widespread infections, and defective neutrophil mobility. Lancet 1979; 01: 1099-1101.
• 50 Weber C. et al. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 2000; 67: 699-704.
• 51 Funderburg NT. et al. Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome. Blood 2012; 120: 4599-4608.
• 52 Giesen PL. et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-2315.
• 53 Belge KU. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002; 168: 3536-3542.
• 54 Nockher WA, Scherberich JE.. Expanded CD14+ CD16+ monocyte subpopulation in patients with acute and chronic infections undergoing hemodialysis. Infection Immunity 1998; 66: 2782-2790.
• 55 Furman MI. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358.
• 56 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.
• 57 Jorissen RN. et al. Additivity in the analysis and design of HIV protease inhibitors. J Med Chem 2009; 52: 737-754.
• 58 Wrigley BJ. et al. Increased formation of monocyte-platelet aggregates in ischemic heart failure. Circ Heart Fail 2013; 06: 127-135.
• 59 Ozaki Y. et al. Association between P-selectin glycoprotein ligand-1 and pathogenesis in acute coronary syndrome assessed by optical coherence tomography. Atherosclerosis 2014; 233: 697-703.
• 60 Shantsila E. et al. Monocytes circulate in constant reversible interaction with platelets in a [Ca2+]-dependent manner. Platelets 2014; 25: 197-201.
• 61 De Palma M. et al Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005; 08: 211-226.
• 62 Coffelt SB. et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010; 70: 5270-5280.
• 63 Cochain C. et al. Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularisation. Cardiovasc Res 2010; 88: 186-195.
• 64 Czepluch FS. et al. In vitro and in vivo effects of human monocytes and their subsets on new vessel formation. Microcirculation 2014; 21: 148-158.
• 65 Carey III JL. et al Flow Cytometry in Clinical Diagnosis (4th edition). 2007. ASCP Press;
• 66 Darzynkiewicz Z.. Essential Cytometry Methods (Reliable Lab Solutions). Academic Press; 2009
• 67 Heimbeck I. et al. Standardized single-platform assay for human monocyte sub-populations: Lower CD14+CD16++ monocytes in females. Cytometry A 2010; 77: 823-830.
• 68 Hearps AC. et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 2012; 11: 867-875.
• 69 Fingerle-Rowson G. et al Expansion of CD14+CD16+ monocytes in critically ill cardiac surgery patients. Inflammation 1998; 22: 367-379.
• 70 Barisione C. et al. CD14CD16 monocyte subset levels in heart failure patients. Dis Markers 2010; 28: 115-124.
• 71 Palframan RT. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med 2001; 194: 1361-1373.
• 72 Ziegler-Heitbrock L. Monocyte subsets in man and other species. Cell Immunol 2014; 289: 135-139.
• 73 Sunderkotter C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 2004; 172: 4410-4417.
• 74 Rosenstein Y. et al. CD43, a molecule with multiple functions. Immunol Res 1999; 20: 89-99.
• 75 Bamezai A.. Mouse Ly-6 proteins and their extended family: markers of cell differentiation and regulators of cell signaling. Arch Immunol Therap Exp 2004; 52: 255-266.
• 76 Geissmann F. et al. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71-82.
• 77 Auffray C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007; 317: 666-670.
• 78 Burke B. et al. Increased TNF expression in CD43++ murine blood monocytes. Immunol Lett 2008; 118: 142-147.
• 79 Ingersoll MA. et al. Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 2010; 115: e10-19.
• 80 Hristov M, Heine GH.. Monocyte subsets in atherosclerosis. Hamostaseologie 2015; 35: 105-112.
• 81 Jaipersad AS. et al. The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 2014; 63: 1-11.
• 82 Ghattas A. et al. Monocytes in coronary artery disease and atherosclerosis: where are we now?. J Am Coll Cardiol 2013; 62: 1541-1551.
• 83 Swirski FK. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
• 84 Nahrendorf M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204: 3037-3047.
• 85 Rogacev KS. 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 chronic kidney disease. Arterioscl Thromb Vasc Biol 2014; 34: 2120-2127.
• 86 Rogacev KS. et al. CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 2011; 32: 84-92.
• 87 Krychtiuk KA. et al. Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a). J Clin Lipidol 2015; 09: 533-541.
• 88 Rothe G. et al. Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. Arterioscl Thromb Vasc Biol 1996; 16: 1437-1447.
• 89 Braesch-Andersen S. et al ApoE production in human monocytes and its regulation by inflammatory cytokines. PloS one 2013; 08: e79908.
• 90 Krychtiuk KA. et al. Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease. Atherosclerosis 2014; 237: 589-596.
• 91 Krychtiuk KA. et al. Association of small dense LDL serum levels and circulating monocyte subsets in stable coronary artery disease. PloS one 2015; 10: e0123367.
• 92 Jaipersad AS. et al. Expression of monocyte subsets and angiogenic markers in relation to carotid plaque neovascularisation in patients with pre-existing coronary artery disease and carotid stenosis. Ann Med 2014; 46: 530-538.
• 93 Kaito M. et al. Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients. PloS one 2013; 08: e69409.
• 94 Urra X. et al. Monocyte subtypes predict clinical course and prognosis in human stroke. J Cerebr Blood Flow Metab 2009; 29: 994-1002.
• 95 Zhou X. et al. High-salt intake induced visceral adipose tissue hypoxia and its association with circulating monocyte subsets in humans. Obesity 2014; 22: 1470-1476.
• 96 Terasawa T. et al. Bezafibrate, a peroxisome proliferator-activated receptor alpha agonist, decreases circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes. Translat Res 2015; 165: 336-345.
• 97 Jaipersad AS. et al. The effect of statin therapy withdrawal on monocyte subsets. Eur J Clin Invest 2013; 43: 1307-1313.
• 98 Mosig 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.
• 99 Rothe G. et al. A more mature phenotype of blood mononuclear phagocytes is induced by fluvastatin treatment in hypercholesterolemic patients with coronary heart disease. Atherosclerosis 1999; 144: 251-261.
• 100 Coen PM. 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 Clin Exp 2010; 59: 1775-1783.
• 101 Imanishi T. et al. Association of monocyte subset counts with coronary fibrous cap thickness in patients with unstable angina pectoris. Atherosclerosis 2010; 212: 628-635.
• 102 Shantsila E. et al. Monocyte subsets in coronary artery disease and their associations with markers of inflammation and fibrinolysis. Atherosclerosis 2014; 234: 4-10.
• 103 Leers MP. et al. The pro- and anticoagulant role of blood-borne phagocytes in patients with acute coronary syndrome. Thromb Haemost 2013; 110: 101-109.
• 104 Wrigley BJ. et al. CD14++CD16+ monocytes in patients with acute ischaemic heart failure. Eur J Clin Invest 2013; 43: 121-130.
• 105 Subimerb C. et al. Circulating CD14(+) CD16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma. Clin Exp Immunol 2010; 161: 471-479.
• 106 Amir O. et al. Changes in the monocytic subsets CD14(dim)CD16(+) and CD14(++)CD16(-) in chronic systolic heart failure patients. Mediators Inflamm 2012; 2012: 616384.
• 107 Berg KE. et al. Elevated CD14++CD16− monocytes predict cardiovascular events. Circ Cardiovasc Genet 2012; 05: 122-131.
• 108 Ghigliotti G. et al. CD16(+) monocyte subsets are increased in large abdominal aortic aneurysms and are differentially related with circulating and cell-associated biochemical and inflammatory biomarkers. Dis Markers 2013; 34: 131-142.