Oxidation-specific epitopes are major targets of innate immunity in atherothrombosis

Zusammenfassung

Atherosklerose ist eine chronisch-entzündliche Erkrankung der Gefäßwände, die durch das Zusammenspiel von Dyslipidämie und vermehrtem oxidativen Stress verursacht wird. Die damit verbundene Lipidperoxidation führt zu einer Reihe von Abbauprodukten von Membranlipiden, sogenannten oxidations-spezifischen Epitopen (OSE). OSE finden sich in oxidierten Lipoproteinen und auf der Oberfläche absterbender Zellen, und ihre Fähigkeit inflammatorische und thrombogene Reaktionen auszulösen ist weithin bekannt. Jüngste Studien konnten zeigen, daß OSE spezifische Zielstrukturen für eine Reihe von zellulären und humoralen Rezeptoren des angeborenen Immunsystems darstellen. Dadurch kann das Immunsystem, metabolische Abbaubprodukte erkennen und wichtige physiologische “Haushaltsfunktionen” vermitteln, z.B. durch die kontrollierte Entsorgung abgestorbener Zellen und oxidierten Moleküle. So wurde gezeigt, daß natürliche IgM Antikörper mit Spezifität für OSE Mäuse vor der Entstehung atherosklerotischer Läsionen schützen. So können spezifische natürliche IgM Antikörper die pro-inflammatorischen und pro-thrombotischen Effekte von OSE neutralisieren, währenddessen niedrige Plasmaspiegel OSE-spezifischer IgM Antikörper mit einem erhöhten Risiko für Myokardinfarkt assoziiert sind. Schlussfolgerung: Das Verständnis der molekularen Komponenten und Mechanismen, die an diesem Prozess beteiligt sind, werden in Zukunft dazu beitragen, Personen mit einem erhöhten Risiko für Atherothrombose besser zu identifizieren und möglicherweise neue therapeutische Ansatzpunkte zu definieren.

Summary

Atherosclerosis is a chronic inflammatory disease of the vascular wall that results from disturbed lipoprotein metabolism and increased oxidative stress. A major consequence of this is lipid peroxidation, which generates a number of breakdown products of membrane lipids that form so called oxidation-specific epitopes (OSE). OSE have been documented in oxidized lipoproteins and on the surface of dying cells and circulating microparticles, and their ability to trigger robust pro-inflammatory and prothrombotic responses has been demonstrated extensively. Recent studies have identified specific OSE as major targets of both cellular and soluble pattern recognition receptors of the innate immune system, including innate natural IgM antibodies. This allows the immune system to identify metabolic waste and mediate important physiological house keeping functions, e.g. by promoting the removal of cellular debris and by neutralizing oxidized molecules. Indeed, innate B1 cells and B1 cell derived natural IgM with specificity for OSE have been shown to protect mice from the development of athero-sclerotic lesions. Moreover, OSE-specific natural IgM antibodies bind and neutralize the pro-inflammatory and pro-thrombotic effects of OSE, and low levels of OSE-specific IgM are associated with an increased risk for myocardial infarction. Conclusion: Understanding the molecular components and mechanisms involved in this process, will help identify individuals with increased risk for atherothrombosis and indicate novel points for therapeutic intervention.

Schlüsselwörter

Atherothrombose - Oxidiertes LDL - angeborene Immunität - natürliche IgM Antikörper

Keywords

Atherothrombosis - oxidized LDL - innate immunity - natural IgM antibodies

• References

• 1 Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 2013; 38: 1092-1104.
• 2 Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol 1997; 17: 1859-1867.
• 3 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
• 4 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
• 5 Rautou PE, Vion AC, Amabile N. et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593-606.
• 6 Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost 2011; 105 (Suppl. 01) S34-S42.
• 7 Nakashima Y, Fujii H, Sumiyoshi S. et al. Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration. Arterioscler Thromb Vasc Biol 2007; 27: 1159-1165.
• 8 Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30: 2311-2316.
• 9 Younis N, Sharma R, Soran H. et al. Glycation as an atherogenic modification of LDL. Curr Opin Lip-idol 2008; 19: 378-384.
• 10 Oorni K, Pentikainen MO, Ala-Korpela M, Kovanen PT. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J Lipid Res 2000; 41: 1703-1714.
• 11 Weismann D, Binder CJ. The innate immune response to products of phospholipid peroxidation. Biochim Biophys Acta 2012; 1818: 2465-2475.
• 12 Miller YI, Choi SH, Wiesner P. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 2011; 108: 235-248.
• 13 Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol 2006; 26: 1702-1711.
• 14 Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res 2014; 114: 1757-1771.
• 15 Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol 2013; 13: 621-634.
• 16 Tabas I, Williams KJ, Boren J. Subendothelial lipo-protein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116: 1832-1844.
• 17 Dei R, Takeda A, Niwa H. et al. Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer’s disease. Acta Neuropathol 2002; 104: 113-122.
• 18 Imai Y, Kuba K, Neely GG. et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008; 133: 235-249.
• 19 Palinski W, Horkko S, Miller E. et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest 1996; 98: 800-814.
• 20 Weismann D, Hartvigsen K, Lauer N. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 2011; 478: 76-81.
• 21 Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001; 1: 135-145.
• 22 Stewart CR, Stuart LM, Wilkinson K. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11: 155-161.
• 23 Duewell P, Kono H, Rayner KJ. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357-1361.
• 24 Chang MK, Bergmark C, Laurila A. et al. 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 1999; 96: 6353-6358.
• 25 Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998; 101: 353-363.
• 26 Chou MY, Fogelstrand L, Hartvigsen K. et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 2009; 119: 1335-1349.
• 27 Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 2010; 10: 778-786.
• 28 Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 2011; 11: 34-46.
• 29 Griffin DO, Holodick NE, Rothstein TL. Human B1 cells are CD3-: A reply to “A human equivalent of mouse B-1 cells?” and “The nature of circulating CD27+CD43+ B cells”. J Exp Med 2011; 208: 2566-2569.
• 30 Bochkov VN, Oskolkova OV, Birukov KG. et al. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal 2010; 12: 1009-1059.
• 31 Lee S, Birukov KG, Romanoski CE. et al. Role of phospholipid oxidation products in atherosclerosis. Circ Res 2012; 111: 778-799.
• 32 Annex BH, Denning SM, Channon KM. et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 1995; 91: 619-622.
• 33 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843.
• 34 Pawlinski R, Wang JG, Owens AP. et al. Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 2010; 116: 806-814.
• 35 Ferro D, Basili S, Alessandri C. et al. Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia. Lancet 1997; 350: 1222.
• 36 Owens AP, 3^rd Mackman N. Sources of tissue factor that contribute to thrombosis after rupture of an atherosclerotic plaque. Thromb Res 2012; 129 (Suppl. 02) S30-S33.
• 37 Mallat Z, Hugel B, Ohan J. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 1999; 99: 348-353.
• 38 Owens AP, 3^rd Passam FH, Antoniak S. et al. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 2012; 122: 558-568.
• 39 Ravandi A, Leibundgut G, Hung MY. et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J Am Coll Cardiol 2014; 63: 1961-1971.
• 40 Tsimikas S, Brilakis ES, Miller ER. et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005; 353: 46-57.
• 41 Podrez EA, Byzova TV, Febbraio M. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 2007; 13: 1086-1095.
• 42 Morel O, Morel N, Jesel L. et al. Microparticles: a critical component in the nexus between inflammation, immunity, and thrombosis. Semin Immunopathol 2011; 33: 469-486.
• 43 Leroyer AS, Isobe H, Leseche G, Castier Y, Wassef M, Mallat Z. et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007; 49: 772-777.
• 44 Barry OP, Pratico D, Lawson JA, FitzGerald GA. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest 1997; 99: 2118-2127.
• 45 Huber J, Vales A, Mitulovic G. et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol 2002; 22: 101-107.
• 46 Chang MK, Binder CJ, Miller YI. et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med 2004; 200: 1359-1370.
• 47 Tsiantoulas D, Perkmann T, Afonyushkin T. et al. Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. J Lipid Res 2015; 56: 440-448.
• 48 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126.
• 49 Lichtman AH, Binder CJ, Tsimikas S, Witztum JL. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 2013; 123: 27-36.
• 50 Stemme S, Faber B, Holm J. et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA 1995; 92: 3893-3897.
• 51 Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. B cells and humoral immunity in atherosclerosis. Circ Res 2014; 114: 1743-1756.
• 52 Boullier A, Gillotte KL, Horkko S. et al. The binding of oxidized low density lipoprotein to mouse CD36 is mediated in part by oxidized phospholipids that are associated with both the lipid and protein moieties of the lipoprotein. J Biol Chem 2000; 275: 9163-9169.
• 53 Horkko S, Bird DA, Miller E. et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipo-proteins. J Clin Invest 1999; 103: 117-128.
• 54 Chen Y, Park YB, Patel E, Silverman GJ. IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J Immunol 2009; 182: 6031-6043.
• 55 Binder CJ, Horkko S, Dewan A. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003; 9: 736-743.
• 56 Faria-Neto JR, Chyu KY, Li X. et al. Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice. Atherosclerosis 2006; 189: 83-90.
• 57 Puurunen M, Manttari M, Manninen V. et al. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch Intern Med 1994; 154: 2605-2609.
• 58 Ahmed E, Trifunovic J, Stegmayr B. et al. Autoanti-bodies against oxidatively modified LDL do not constitute a risk factor for stroke: a nested case-control study. Stroke 1999; 30: 2541-2546.
• 59 Tsimikas S, Brilakis ES, Lennon RJ. et al. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res 2007; 48: 425-433.
• 60 Sjoberg BG, Su J, Dahlbom I. et al. Low levels of IgM antibodies against phosphorylcholine-A potential risk marker for ischemic stroke in men. Atherosclerosis 2009; 203: 528-532.
• 61 Gronlund H, Hallmans G, Jansson JH. et al. Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden. Eur J Cardiovasc Prev Rehabil 2009; 16: 382-386.
• 62 Tsimikas S, Willeit P, Willeit J. et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60: 2218-2229.