Jump to ContentJump to Main Navigation
Show Summary Details
More options …


Editor-in-Chief: Pelegrin, Pablo

Ed. by Lopez-Castejón, Gloria

1 Issue per year

Emerging Science

Open Access
See all formats and pricing
More options …

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

Maria Teresa Montero-Vega
  • Corresponding author
  • Department of Research in Biochemistry, Ramón y Cajal Institute for Health Research (IRYCIS), Ramón y Cajal University Hospital, Ctra. Colmenar, km 9, 28034 Madrid, Spain
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-10-10 | DOI: https://doi.org/10.2478/infl-2014-0006


Low-density lipoproteins become oxidised (ox-LDL) when retained in the arterial intima and are considered to be the inducers of inflammation in atherosclerosis. Peroxidation of phospholipids generates a variety of oxidised molecules in LDL and leads to the formation of oxidised lipid-protein adducts. These oxidative modifications are the target of various pattern recognition receptors (PRRs) and constitute immunogenic neoepitopes, termed oxidation-specific epitopes (OSEs). OSEs are thought to be a class of danger-associated molecular patterns (DAMPs) that mediate pro-inflammatory signals in atherosclerosis. Nevertheless, identical OSEs are generated on apoptotic cells that are identified by innate immunity through the same receptors to promote housekeeping tasks and immunosuppression. The present study provides an alternative point of view and proposes that OSEs are ‘waste-associated molecular patterns’ (WAMPs) recognised by innate immunity as a signal for the presence of oxidised waste that must be cleared without triggering inflammation. The hypothesis presented here states that ox-LDL are not inflammatory per se but instead polarise macrophages for housekeeping functions; however, other immune alerts, which are generated under the influence of risk factors, cooperate with them in switching macrophage polarisation towards dangerous phenotypes that complicate atheromas with different tendencies. This hypothesis of ‘immune cooperation’ explains why atheromas grow silently for decades and reveals atherosclerosis to be a dynamic disease that begins with the retention and oxidation of LDL in the arterial intima and ends with the formation of a thrombus, but in which the underlying immune process changes over time and differs between patients.

Keywords : oxidation-specific epitopes; natural antibodies; cardiovascular disease; M1 M2 macrophage; risk factors


  • [1] Ross R., Glomset J., Harker L., Response to injury and atherogenesis, Am J Pathol, 1977, 86, 675-684. Google Scholar

  • [2] Ross R., Atherosclerosis--an inflammatory disease, N Engl J Med, 1999, 340, 115-126. Google Scholar

  • [3] Tabas I., Williams K.J., Boren J., Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications, Circulation, 2007, 116, 1832-1844. CrossrefGoogle Scholar

  • [4] Kzhyshkowska J., Neyen C., Gordon S., Role of macrophage scavenger receptors in atherosclerosis, Immunobiology, 2012, 217, 492-502. Google Scholar

  • [5] Yu X.H., Fu Y.C., Zhang D.W., Yin K., Tang C.K., Foam cells in atherosclerosis, Clin Chim Acta, 2013, 424, 245-252. Google Scholar

  • [6] Moore K.J., Sheedy F.J., Fisher E.A., Macrophages in atherosclerosis: a dynamic balance, Nat Rev Immunol, 2013, 13, 709-721. CrossrefGoogle Scholar

  • [7] Leibundgut G., Witztum J.L., Tsimikas S., Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis, Curr Opin Pharmacol, 2013, 13, 168-179. CrossrefGoogle Scholar

  • [8] Miller Y.I., Choi S.H., Wiesner P., Fang L., Harkewicz R., Hartvigsen K., Boullier A., Gonen A., Diehl C.J., Que X., et al., Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity, Circ Res, 2011, 108, 235-248. CrossrefGoogle Scholar

  • [9] Weismann D., Binder C.J., The innate immune response to products of phospholipid peroxidation, Biochim Biophys Acta, 2012, 1818, 2465-2475. Google Scholar

  • [10] Witztum J.L., Lichtman A.H., The influence of innate and adaptive immune responses on atherosclerosis, Annu Rev Pathol, 2014, 9, 73-102. CrossrefGoogle Scholar

  • [11] Gallucci S., Matzinger P., Danger signals: SOS to the immune system, Curr Opin Immunol, 2001, 13, 114-119. CrossrefGoogle Scholar

  • [12] Bianchi M.E., DAMPs, PAMPs and alarmins: all we need to know about danger, J Leukoc Biol, 2007, 81, 1-5. Google Scholar

  • [13] Boullier A., Gillotte K.L., Horkko S., Green S.R., Friedman P., Dennis E.A., Witztum J.L., Steinberg D., Quehenberger O., 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. Google Scholar

  • [14] Podrez E.A., Poliakov E., Shen Z., Zhang R., Deng Y., Sun M., Finton P.J., Shan L., Febbraio M., Hajjar D.P., et al., A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions, J Biol Chem, 2002, 277, 38517-38523. Google Scholar

  • [15] Boullier A., Friedman P., Harkewicz R., Hartvigsen K., Green S.R., Almazan F., Dennis E.A., Steinberg D., Witztum J.L., Quehenberger O., Phosphocholine as a pattern recognition ligand for CD36, J Lipid Res, 2005, 46, 969-976. CrossrefGoogle Scholar

  • [16] Chou M.Y., Hartvigsen K., Hansen L.F., Fogelstrand L., Shaw P.X., Boullier A., Binder C.J., Witztum J.L., Oxidation-specific epitopes are important targets of innate immunity, J Intern Med, 2008, 263, 479-488. Google Scholar

  • [17] Lee S., Birukov K.G., Romanoski C.E., Springstead J.R., Lusis A.J., Berliner J.A., Role of phospholipid oxidation products in atherosclerosis, Circ Res, 2012, 111, 778-799. CrossrefGoogle Scholar

  • [18] Podrez E.A., Poliakov E., Shen Z., Zhang R., Deng Y., Sun M., Finton P.J., Shan L., Gugiu B., Fox P.L., et al., Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36, J Biol Chem, 2002, 277, 38503-38516. Google Scholar

  • [19] Li X.M., Salomon R.G., Qin J., Hazen S.L., Conformation of an endogenous ligand in a membrane bilayer for the macrophage scavenger receptor CD36, Biochemistry, 2007, 46, 5009-5017. CrossrefGoogle Scholar

  • [20] Gao D., Ashraf M.Z., Kar N.S., Lin D., Sayre L.M., Podrez E.A., Structural basis for the recognition of oxidized phospholipids in oxidized low density lipoproteins by class B scavenger receptors CD36 and SR-BI, J Biol Chem, 2010, 285, 4447-4454. Google Scholar

  • [21] Greenberg M.E., Li X.M., Gugiu B.G., Gu X., Qin J., Salomon R.G., Hazen S.L., The lipid whisker model of the structure of oxidized cell membranes, J Biol Chem, 2008, 283, 2385-2396. Google Scholar

  • [22] Ufer C., Wang C.C., Borchert A., Heydeck D., Kuhn H., Redox control in mammalian embryo development, Antioxid Redox Signal, 2010, 13, 833-875. Google Scholar

  • [23] Thompson L.P., Al-Hasan Y., Impact of oxidative stress in fetal programming, J Pregnancy, 2012, 2012, 582748. Google Scholar

  • [24] Bochkov V.N., Oskolkova O.V., Birukov K.G., Levonen A.L., Binder C.J., Stockl J., Generation and biological activities of oxidized phospholipids, Antioxid Redox Signal, 2010, 12, 1009-1059. Google Scholar

  • [25] Tsiantoulas D., Gruber S., Binder C.J., B-1 cell immunoglobulin directed against oxidation-specific epitopes, Front Immunol, 2013, 3, 415. Google Scholar

  • [26] Davies S.S., Guo L., Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids, Chem Phys Lipids, 2014, 181C, 1-33. Google Scholar

  • [27] Salomon R.G., Structural identification and cardiovascular activities of oxidized phospholipids, Circ Res, 2012, 111, 930-946. CrossrefGoogle Scholar

  • [28] Levitan I., Volkov S., Subbaiah P.V., Oxidized LDL: diversity, patterns of recognition, and pathophysiology, Antioxid Redox Signal, 2010, 13, 39-75. Google Scholar

  • [29] Leonarduzzi G., Gamba P., Gargiulo S., Biasi F., Poli G., Inflammation-related gene expression by lipid oxidationderived products in the progression of atherosclerosis, Free Radic Biol Med, 2012, 52, 19-34. Google Scholar

  • [30] Greig F.H., Kennedy S., Spickett C.M., Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation, Free Radic Biol Med, 2012, 52, 266-280. Google Scholar

  • [31] Aldrovandi M., O’Donnell V.B., Oxidized PLs and vascular inflammation, Curr Atheroscler Rep, 2013, 15, 323. CrossrefGoogle Scholar

  • [32] Williams H.J., Fisher E.A., Greaves D.R., Macrophage differentiation and function in atherosclerosis: opportunities for therapeutic intervention?, J Innate Immun, 2012, 4, 498-508. CrossrefGoogle Scholar

  • [33] Frisdal E., Lesnik P., Olivier M., Robillard P., Chapman M.J., Huby T., Guerin M., Le Goff W., Interleukin-6 protects human macrophages from cellular cholesterol accumulation and attenuates the proinflammatory response, J Biol Chem, 2011, 286, 30926-30936. CrossrefGoogle Scholar

  • [34] Erridge C., The roles of Toll-like receptors in atherosclerosis, J Innate Immun, 2009, 1, 340-349. CrossrefGoogle Scholar

  • [35] Seneviratne A.N., Sivagurunathan B., Monaco C., Toll-like receptors and macrophage activation in atherosclerosis, Clin Chim Acta, 2012, 413, 3-14. Google Scholar

  • [36] Cole J.E., Kassiteridi C., Monaco C., Toll-like receptors in atherosclerosis: a ‘Pandora’s box’ of advances and controversies, Trends Pharmacol Sci, 2013, 34, 629-636. CrossrefGoogle Scholar

  • [37] Birukov K.G., Oxidized lipids: the two faces of vascular inflammation, Curr Atheroscler Rep, 2006, 8, 223-231. CrossrefGoogle Scholar

  • [38] Silverstein R.L., Febbraio M., CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior, Sci Signal, 2009, 2, re3. CrossrefGoogle Scholar

  • [39] Seimon T.A., Nadolski M.J., Liao X., Magallon J., Nguyen M., Feric N.T., Koschinsky M.L., Harkewicz R., Witztum J.L., Tsimikas S., et al., Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress, Cell Metab, 2012, 12, 467-482. Google Scholar

  • [40] Feige E., Mendel I., George J., Yacov N., Harats D., Modified phospholipids as anti-inflammatory compounds, Curr Opin Lipidol, 2010, 21, 525-529. CrossrefGoogle Scholar

  • [41] Egger J., Bretscher P., Freigang S., Kopf M., Carreira E.M., Synthesis of epoxyisoprostanes: effects in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12, Angew Chem Int Ed Engl, 2013, 52, 5382-5385. CrossrefGoogle Scholar

  • [42] Li L., Wang X.P., Wu K., The therapeutic effect of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine in rodents with acute necrotizing pancreatitis and its mechanism, Pancreas, 2007, 35, e27-36. CrossrefGoogle Scholar

  • [43] Matt U., Sharif O., Martins R., Furtner T., Langeberg L., Gawish R., Elbau I., Zivkovic A., Lakovits K., Oskolkova O., et al., WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs, J Clin Invest, 2013, 123, 3014-3024. CrossrefGoogle Scholar

  • [44] Knapp S., Matt U., Leitinger N., van der Poll T., Oxidized phospholipids inhibit phagocytosis and impair outcome in gram-negative sepsis in vivo, J Immunol, 2007, 178, 993-1001. Google Scholar

  • [45] Canton J., Neculai D., Grinstein S., Scavenger receptors in homeostasis and immunity, Nat Rev Immunol, 2013, 13, 621-634. CrossrefGoogle Scholar

  • [46] Varga T., Czimmerer Z., Nagy L., PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation, Biochim Biophys Acta, 2011, 1812, 1007-1022. Google Scholar

  • [47] Kadl A., Meher A.K., Sharma P.R., Lee M.Y., Doran A.C., Johnstone S.R., Elliott M.R., Gruber F., Han J., Chen W., et al., Identification of a Novel Macrophage Phenotype That Develops in Response to Atherogenic Phospholipids via Nrf2, Circ Res, 2010, 107, 737-746. CrossrefGoogle Scholar

  • [48] Hybertson B.M., Gao B., Bose S.K., McCord J.M., Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation, Mol Aspects Med, 2011, 32, 234-246. CrossrefGoogle Scholar

  • [49] Kim J., Cha Y.N., Surh Y.J., A protective role of nuclear factorerythroid 2-related factor-2 (Nrf2) in inflammatory disorders, Mutat Res, 2010, 690, 12-23. Google Scholar

  • [50] Cherepanova O.A., Pidkovka N.A., Sarmento O.F., Yoshida T., Gan Q., Adiguzel E., Bendeck M.P., Berliner J., Leitinger N., Owens G.K., Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration, Circ Res, 2009, 104, 609-618. CrossrefGoogle Scholar

  • [51] Chovatiya R., Medzhitov R., Stress, inflammation, and defense of homeostasis, Mol Cell, 2014, 54, 281-288. CrossrefGoogle Scholar

  • [52] Devitt A., Marshall L.J., The innate immune system and the clearance of apoptotic cells, J Leukoc Biol, 2011, 90, 447-457. CrossrefGoogle Scholar

  • [53] Mold J.E., McCune J.M., At the crossroads between tolerance and aggression: Revisiting the “layered immune system” hypothesis, Chimerism, 2011, 2, 35-41. CrossrefGoogle Scholar

  • [54] Zhang X., Regulatory functions of innate-like B cells, Cell Mol Immunol, 2013, 10, 113-121. Google Scholar

  • [55] Baumgarth N., The double life of a B-1 cell: self-reactivity selects for protective effector functions, Nat Rev Immunol, 2011, 11, 34-46. Google Scholar

  • [56] Avrameas S., Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’, Immunol Today, 1991, 12, 154-159. Google Scholar

  • [57] Baumgarth N., Tung J.W., Herzenberg L.A., Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion, Springer Semin Immunopathol, 2005, 26, 347-362. CrossrefGoogle Scholar

  • [58] Avrameas S., Selmi C., Natural autoantibodies in the physiology and pathophysiology of the immune system, J Autoimmun, 2013, 41, 46-49. CrossrefGoogle Scholar

  • [59] Elkon K.B., Silverman G.J., Naturally occurring autoantibodies to apoptotic cells, Adv Exp Med Biol, 2012, 750, 14-26. Google Scholar

  • [60] Kaveri S.V., Silverman G.J., Bayry J., Natural IgM in immune equilibrium and harnessing their therapeutic potential, J Immunol, 2012, 188, 939-945. Google Scholar

  • [61] Poon I.K., Lucas C.D., Rossi A.G., Ravichandran K.S., Apoptotic cell clearance: basic biology and therapeutic potential, Nat Rev Immunol, 2014, 14, 166-180. CrossrefGoogle Scholar

  • [62] Gregory C.D., Devitt A., The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically?, Immunology, 2004, 113, 1-14. CrossrefGoogle Scholar

  • [63] Wang C., Turunen S.P., Kummu O., Veneskoski M., Lehtimaki J., Nissinen A.E., Horkko S., Natural antibodies of newborns recognize oxidative stress-related malondialdehyde acetaldehyde adducts on apoptotic cells and atherosclerotic plaques, Int Immunol, 2013, 25, 575-587. CrossrefGoogle Scholar

  • [64] Tsiantoulas D., Diehl C.J., Witztum J.L., Binder C.J., B Cells and Humoral Immunity in Atherosclerosis, Circ Res, 2014, 114, 1743-1756. CrossrefGoogle Scholar

  • [65] Bonacina F., Baragetti A., Catapano A.L., Norata G.D., Long pentraxin 3: experimental and clinical relevance in cardiovascular diseases, Mediators Inflamm, 2013, 2013, 725102. Google Scholar

  • [66] Gershov D., Kim S., Brot N., Elkon K.B., C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity, J Exp Med, 2000, 192, 1353-1364. CrossrefGoogle Scholar

  • [67] Norata G.D., Garlanda C., Catapano A.L., The long pentraxin PTX3: a modulator of the immunoinflammatory response in atherosclerosis and cardiovascular diseases, Trends Cardiovasc Med, 2010, 20, 35-40. CrossrefGoogle Scholar

  • [68] Fraser D.A., Tenner A.J., Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages, J Immunol, 2010, 185, 3932-3939. Google Scholar

  • [69] O’Donnell V.B., Murphy R.C., New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions, Blood, 2012, 120, 1985-1992. CrossrefGoogle Scholar

  • [70] Cruz D., Watson A.D., Miller C.S., Montoya D., Ochoa M.T., Sieling P.A., Gutierrez M.A., Navab M., Reddy S.T., Witztum J.L., et al., Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy, J Clin Invest, 2008, 118, 2917-2928. CrossrefGoogle Scholar

  • [71] N A.G., Hidalgo A., Nuclear Receptors and Clearance of Apoptotic Cells: Stimulating the Macrophage’s Appetite, Front Immunol, 2014, 5, 211. Google Scholar

  • [72] Bournazou I., Pound J.D., Duffin R., Bournazos S., Melville L.A., Brown S.B., Rossi A.G., Gregory C.D., Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin, J Clin Invest, 2009, 119, 20-32. Google Scholar

  • [73] Montero Vega M.T., de Andres Martin A., The significance of toll-like receptors in human diseases, Allergol Immunopathol (Madr), 2009, 37, 252-263. Google Scholar

  • [74] Martin C., Chevrot M., Poirier H., Passilly-Degrace P., Niot I., Besnard P., CD36 as a lipid sensor, Physiol Behav, 2011, 105, 36-42. CrossrefGoogle Scholar

  • [75] Oh J., Riek A.E., Weng S., Petty M., Kim D., Colonna M., Cella M., Bernal-Mizrachi C., Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation, J Biol Chem, 2012, 287, 11629-11641. Google Scholar

  • [76] Montero-Vega M.T., The inflammatory process underlying atherosclerosis, Crit Rev Immunol, 2012, 32, 373-462. CrossrefGoogle Scholar

  • [77] Aird W.C., Phenotypic heterogeneity of the endothelium: II. Representative vascular beds, Circ Res, 2007, 100, 174-190. CrossrefGoogle Scholar

  • [78] Aird W.C., Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms, Circ Res, 2007, 100, 158-173. CrossrefGoogle Scholar

  • [79] Zarins C.K., Giddens D.P., Bharadvaj B.K., Sottiurai V.S., Mabon R.F., Glagov S., Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress, Circ Res, 1983, 53, 502-514. CrossrefGoogle Scholar

  • [80] Pryshchep O., Ma-Krupa W., Younge B.R., Goronzy J.J., Weyand C.M., Vessel-specific Toll-like receptor profiles in human medium and large arteries, Circulation, 2008, 118, 1276-1284. CrossrefGoogle Scholar

  • [81] Sorensen K.K., McCourt P., Berg T., Crossley C., Le Couteur D., Wake K., Smedsrod B., The scavenger endothelial cell: a new player in homeostasis and immunity, Am J Physiol Regul Integr Comp Physiol, 2012, 303, R1217-1230. Google Scholar

  • [82] Opitz B., Eitel J., Meixenberger K., Suttorp N., Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections, Thromb Haemost, 2009, 102, 1103-1109. Google Scholar

  • [83] Yamamoto K., Ando J., New molecular mechanisms for cardiovascular disease:blood flow sensing mechanism in vascular endothelial cells, J Pharmacol Sci, 2011, 116, 323-331. CrossrefGoogle Scholar

  • [84] Hahn C., Schwartz M.A., Mechanotransduction in vascular physiology and atherogenesis, Nat Rev Mol Cell Biol, 2009, 10, 53-62. CrossrefGoogle Scholar

  • [85] Harrington L.S., Belcher E., Moreno L., Carrier M.J., Mitchell J.A., Homeostatic role of Toll-like receptor 4 in the endothelium and heart, J Cardiovasc Pharmacol Ther, 2007, 12, 322-326. CrossrefGoogle Scholar

  • [86] Mullick A.E., Soldau K., Kiosses W.B., Bell T.A., 3rd, Tobias P.S., Curtiss L.K., Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events, J Exp Med, 2008, 205, 373-383. Google Scholar

  • [87] Curtiss L.K., Tobias P.S., Emerging role of Toll-like receptors in atherosclerosis, J Lipid Res, 2009, 50 Suppl, S340-345. Google Scholar

  • [88] Yang Q.W., Mou L., Lv F.L., Wang J.Z., Wang L., Zhou H.J., Gao D., Role of Toll-like receptor 4/NF-kappaB pathway in monocyteendothelial adhesion induced by low shear stress and ox-LDL, Biorheology, 2005, 42, 225-236. Google Scholar

  • [89] Dunzendorfer S., Lee H.K., Tobias P.S., Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity, Circ Res, 2004, 95, 684-691. Google Scholar

  • [90] Edfeldt K., Swedenborg J., Hansson G.K., Yan Z.Q., Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation, Circulation, 2002, 105, 1158-1161. Google Scholar

  • [91] Apostolov E.O., Basnakian A.G., Ok E., Shah S.V., Carbamylated low-density lipoprotein: nontraditional risk factor for cardiovascular events in patients with chronic kidney disease, J Ren Nutr, 2012, 22, 134-138. CrossrefGoogle Scholar

  • [92] Yan S.F., Ramasamy R., Schmidt A.M., The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease, Expert Rev Mol Med, 2009, 11, e9. CrossrefGoogle Scholar

  • [93] Yan S.F., Ramasamy R., Schmidt A.M., Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response, J Mol Med (Berl), 2009, 87, 235-247. CrossrefGoogle Scholar

  • [94] Shao B., Oda M.N., Oram J.F., Heinecke J.W., Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein, Chem Res Toxicol, 2010, 23, 447-454. CrossrefGoogle Scholar

  • [95] Wang Z., Nicholls S.J., Rodriguez E.R., Kummu O., Horkko S., Barnard J., Reynolds W.F., Topol E.J., DiDonato J.A., Hazen S.L., Protein carbamylation links inflammation, smoking, uremia and atherogenesis, Nat Med, 2007, 13, 1176-1184. CrossrefGoogle Scholar

  • [96] Apostolov E.O., Shah S.V., Ok E., Basnakian A.G., Quantification of carbamylated LDL in human sera by a new sandwich ELISA, Clin Chem, 2005, 51, 719-728. CrossrefGoogle Scholar

  • [97] Apostolov E.O., Ray D., Savenka A.V., Shah S.V., Basnakian A.G., Chronic uremia stimulates LDL carbamylation and atherosclerosis, J Am Soc Nephrol, 2010, 21, 1852-1857. CrossrefGoogle Scholar

  • [98] Pirillo A., Norata G.D., Catapano A.L., LOX-1, OxLDL, and atherosclerosis, Mediators Inflamm, 2013, 2013, 152786. Google Scholar

  • [99] Apostolov E.O., Ok E., Burns S., Nawaz S., Savenka A., Shah S., Basnakian A.G., Carbamylated-oxidized LDL: proatherosclerotic effects on endothelial cells and macrophages, J Atheroscler Thromb, 2013, 20, 878-892. CrossrefGoogle Scholar

  • [100] Apostolov E.O., Shah S.V., Ray D., Basnakian A.G., Scavenger receptors of endothelial cells mediate the uptake and cellular proatherogenic effects of carbamylated LDL, Arterioscler Thromb Vasc Biol, 2009, 29, 1622-1630. CrossrefGoogle Scholar

  • [101] Nakashima Y., Wight T.N., Sueishi K., Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans, Cardiovasc Res, 2008, 79, 14-23. CrossrefGoogle Scholar

  • [102] Owens G.K., Kumar M.S., Wamhoff B.R., Molecular regulation of vascular smooth muscle cell differentiation in development and disease, Physiol Rev, 2004, 84, 767-801. CrossrefGoogle Scholar

  • [103] Orr A.W., Hastings N.E., Blackman B.R., Wamhoff B.R., Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis, J Vasc Res, 2010, 47, 168-180. CrossrefGoogle Scholar

  • [104] Allahverdian S., Chehroudi A.C., McManus B.M., Abraham T., Francis G.A., Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis, Circulation, 2014, 129, 1551-1559. CrossrefGoogle Scholar

  • [105] Matzinger P., The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor, Expert Rev Clin Immunol, 2012, 8, 311-317. CrossrefGoogle Scholar

  • [106] Stary H.C., Chandler A.B., Glagov S., Guyton J.R., Insull W., Jr., Rosenfeld M.E., Schaffer S.A., Schwartz C.J., Wagner W.D., Wissler R.W., A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association, Arterioscler Thromb, 1994, 14, 840-856. CrossrefGoogle Scholar

  • [107] Steinberg D., Witztum J.L., Oxidized low-density lipoprotein and atherosclerosis, Arterioscler Thromb Vasc Biol, 2010, 30, 2311-2316. CrossrefGoogle Scholar

  • [108] Randolph G.J., Mechanisms That Regulate Macrophage Burden in Atherosclerosis, Circ Res, 2014, 114, 1757-1771. CrossrefGoogle Scholar

  • [109] Leitinger N., Tyner T.R., Oslund L., Rizza C., Subbanagounder G., Lee H., Shih P.T., Mackman N., Tigyi G., Territo M.C., et al., Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils, Proc Natl Acad Sci U S A, 1999, 96, 12010-12015. CrossrefGoogle Scholar

  • [110] Spagnoli L.G., Bonanno E., Sangiorgi G., Mauriello A., Role of inflammation in atherosclerosis, J Nucl Med, 2007, 48, 1800-1815. CrossrefGoogle Scholar

  • [111] Bouhlel M.A., Derudas B., Rigamonti E., Dievart R., Brozek J., Haulon S., Zawadzki C., Jude B., Torpier G., Marx N., et al., PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties, Cell Metab, 2007, 6, 137-143. CrossrefGoogle Scholar

  • [112] Brocheriou I., Maouche S., Durand H., Braunersreuther V., Le Naour G., Gratchev A., Koskas F., Mach F., Kzhyshkowska J., Ninio E., Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: implication in atherosclerosis, Atherosclerosis, 2011, 214, 316-324. Google Scholar

  • [113] Waldo S.W., Li Y., Buono C., Zhao B., Billings E.M., Chang J., Kruth H.S., Heterogeneity of human macrophages in culture and in atherosclerotic plaques, Am J Pathol, 2008, 172, 1112-1126. Google Scholar

  • [114] Khallou-Laschet J., Varthaman A., Fornasa G., Compain C., Gaston A.T., Clement M., Dussiot M., Levillain O., Graff-Dubois S., Nicoletti A., et al., Macrophage plasticity in experimental atherosclerosis, PLoS One, 2010, 5, e8852. CrossrefGoogle Scholar

  • [115] Chinetti-Gbaguidi G., Baron M., Bouhlel M.A., Vanhoutte J., Copin C., Sebti Y., Derudas B., Mayi T., Bories G., Tailleux A., et al., Human Atherosclerotic Plaque Alternative Macrophages Display Low Cholesterol Handling but High Phagocytosis Because of Distinct Activities of the PPAR{gamma} and LXR{alpha} Pathways, Circ Res, 2011, 108, 985-995. CrossrefGoogle Scholar

  • [116] Stoger J.L., Goossens P., de Winther M.P., Macrophage Heterogeneity: Relevance and Functional Implications in Atherosclerosis, Curr Vasc Pharmacol, 2010, CrossrefGoogle Scholar

  • [117] Stoger J.L., Gijbels M.J., van der Velden S., Manca M., van der Loos C.M., Biessen E.A., Daemen M.J., Lutgens E., de Winther M.P., Distribution of macrophage polarization markers in human atherosclerosis, Atherosclerosis, 2012, 225, 461-468. Google Scholar

  • [118] Feig J.E., Vengrenyuk Y., Reiser V., Wu C., Statnikov A., Aliferis C.F., Garabedian M.J., Fisher E.A., Puig O., Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome, PLoS One, 2012, 7, e39790. CrossrefGoogle Scholar

  • [119] Cardilo-Reis L., Gruber S., Schreier S.M., Drechsler M., Papac- Milicevic N., Weber C., Wagner O., Stangl H., Soehnlein O., Binder C.J., Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype, EMBO Mol Med, 2012, 4, 1072-1086. Google Scholar

  • [120] Koltsova E.K., Hedrick C.C., Ley K., Myeloid cells in atherosclerosis: a delicate balance of anti-inflammatory and proinflammatory mechanisms, Curr Opin Lipidol, 2013, 24, 371-380. Google Scholar

  • [121] Mantovani A., Garlanda C., Locati M., Macrophage diversity and polarization in atherosclerosis: a question of balance, Arterioscler Thromb Vasc Biol, 2009, 29, 1419-1423. CrossrefGoogle Scholar

  • [122] Fernandez-Velasco M., Gonzalez-Ramos S., Bosca L., Involvement of monocytes/macrophages as key factors in the development and progression of cardiovascular diseases, Biochem J, 2014, 458, 187-193. Google Scholar

  • [123] Kockx M.M., De Meyer G.R., Muhring J., Jacob W., Bult H., Herman A.G., Apoptosis and related proteins in different stages of human atherosclerotic plaques, Circulation, 1998, 97, 2307-2315. CrossrefGoogle Scholar

  • [124] Tabas I., Macrophage death and defective inflammation resolution in atherosclerosis, Nat Rev Immunol, 2010, 10, 36-46. Google Scholar

  • [125] Thorp E., Subramanian M., Tabas I., The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis, Eur J Immunol, 2011, 41, 2515-2518. CrossrefGoogle Scholar

  • [126] Zheng Y., Gardner S.E., Clarke M.C., Cell death, damageassociated molecular patterns, and sterile inflammation in cardiovascular disease, Arterioscler Thromb Vasc Biol, 2011, 31, 2781-2786. CrossrefGoogle Scholar

  • [127] Hodgkinson C.P., Laxton R.C., Patel K., Ye S., Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis, Arterioscler Thromb Vasc Biol, 2008, 28, 2275-2281. CrossrefGoogle Scholar

  • [128] Sima A.V., Botez G.M., Stancu C.S., Manea A., Raicu M., Simionescu M., Effect of irreversibly glycated LDL in human vascular smooth muscle cells: lipid loading, oxidative and inflammatory stress, J Cell Mol Med, 2010, 14, 2790-2802. CrossrefGoogle Scholar

  • [129] Perrin-Cocon L., Diaz O., Andre P., Lotteau V., Modified lipoproteins provide lipids that modulate dendritic cell immune function, Biochimie, 2013, 95, 103-108. CrossrefGoogle Scholar

  • [130] Curtiss L.K., Black A.S., Bonnet D.J., Tobias P.S., Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists, J Lipid Res, 2012, 53, 2126-2132. CrossrefGoogle Scholar

  • [131] Stewart C.R., Stuart L.M., Wilkinson K., van Gils J.M., Deng J., Halle A., Rayner K.J., Boyer L., Zhong R., Frazier W.A., et al., CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer, Nat Immunol, 2010, 11, 155-161. CrossrefGoogle Scholar

  • [132] Hurst J., von Landenberg P., Toll-like receptors and autoimmunity, Autoimmun Rev, 2008, 7, 204-208. CrossrefGoogle Scholar

  • [133] Mills K.H., TLR-dependent T cell activation in autoimmunity, Nat Rev Immunol, 2011, 11, 807-822. Google Scholar

  • [134] Symmons D.P., Gabriel S.E., Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE, Nat Rev Rheumatol, 2011, 7, 399-408. CrossrefGoogle Scholar

  • [135] Sasaki N., Yamashita T., Takeda M., Hirata K., Regulatory T cells in atherogenesis, J Atheroscler Thromb, 2012, 19, 503-515. CrossrefGoogle Scholar

  • [136] Herbin O., Ait-Oufella H., Yu W., Fredrikson G.N., Aubier B., Perez N., Barateau V., Nilsson J., Tedgui A., Mallat Z., Regulatory T-cell response to apolipoprotein B100-derived peptides reduces the development and progression of atherosclerosis in mice, Arterioscler Thromb Vasc Biol, 2012, 32, 605-612. CrossrefGoogle Scholar

  • [137] Goodman W.A., Cooper K.D., McCormick T.S., Regulation generation: the suppressive functions of human regulatory T cells, Crit Rev Immunol, 2012, 32, 65-79. CrossrefGoogle Scholar

  • [138] Virella G., Lopes-Virella M.F., The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes, Front Endocrinol (Lausanne), 2012, 3, 76. Google Scholar

  • [139] Shimoni S., Bar I., Zilberman L., George J., Autoantibodies to oxidized low-density lipoprotein in patients with aortic regurgitation: association with aortic diameter size, Cardiology, 2014, 128, 54-61. CrossrefGoogle Scholar

  • [140] Shi J., van Veelen P.A., Mahler M., Janssen G.M., Drijfhout J.W., Huizinga T.W., Toes R.E., Trouw L.A., Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies, Autoimmun Rev, 2014, 13, 225-230. CrossrefGoogle Scholar

  • [141] Ordovas-Montanes J.M., Ordovas J.M., Cholesterol, Inflammasomes, and Atherogenesis, Curr Cardiovasc Risk Rep, 2012, 6, 45-52. Google Scholar

  • [142] Yajima N., Takahashi M., Morimoto H., Shiba Y., Takahashi Y., Masumoto J., Ise H., Sagara J., Nakayama J., Taniguchi S., et al., Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice, Circulation, 2008, 117, 3079-3087. CrossrefGoogle Scholar

  • [143] Salminen A., Ojala J., Kaarniranta K., Kauppinen A., Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases, Cell Mol Life Sci, 2012, 69, 2999-3013. CrossrefGoogle Scholar

  • [144] Madamanchi N.R., Runge M.S., Mitochondrial dysfunction in atherosclerosis, Circ Res, 2007, 100, 460-473. CrossrefGoogle Scholar

  • [145] Duewell P., Kono H., Rayner K.J., Sirois C.M., Vladimer G., Bauernfeind F.G., Abela G.S., Franchi L., Nunez G., Schnurr M., et al., NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals, Nature, 2010, 464, 1357-1361. Google Scholar

  • [146] Grebe A., Latz E., Cholesterol crystals and inflammation, Curr Rheumatol Rep, 2013, 15, 313. CrossrefGoogle Scholar

  • [147] Sheedy F.J., Grebe A., Rayner K.J., Kalantari P., Ramkhelawon B., Carpenter S.B., Becker C.E., Ediriweera H.N., Mullick A.E., Golenbock D.T., et al., CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation, Nat Immunol, 2013, 14, 812-820. CrossrefGoogle Scholar

  • [148] Rajamaki K., Lappalainen J., Oorni K., Valimaki E., Matikainen S., Kovanen P.T., Eklund K.K., Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation, PLoS One, 2010, 5, e11765. Google Scholar

  • [149] Menu P., Pellegrin M., Aubert J.F., Bouzourene K., Tardivel A., Mazzolai L., Tschopp J., Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome, Cell Death Dis, 2011, 2, e137. Google Scholar

  • [150] Usui F., Shirasuna K., Kimura H., Tatsumi K., Kawashima A., Karasawa T., Hida S., Sagara J., Taniguchi S., Takahashi M., Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice, Biochem Biophys Res Commun, 2012, 425, 162-168. Google Scholar

  • [151] Montero M.T., Hernandez O., Suarez Y., Matilla J., Ferruelo A.J., Martinez-Botas J., Gomez-Coronado D., Lasuncion M.A., Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and Th1-cytokine release in peripheral blood mononuclear cells, Atherosclerosis, 2000, 153, 303-313. Google Scholar

  • [152] Montero M.T., Matilla J., Gomez-Mampaso E., Lasuncion M.A., Geranylgeraniol regulates negatively caspase-1 autoprocessing: implication in the Th1 response against Mycobacterium tuberculosis, J Immunol, 2004, 173, 4936-4944. CrossrefGoogle Scholar

  • [153] Mandey S.H., Kuijk L.M., Frenkel J., Waterham H.R., A role for geranylgeranylation in interleukin-1beta secretion, Arthritis Rheum, 2006, 54, 3690-3695. CrossrefGoogle Scholar

  • [154] Liao Y.H., Lin Y.C., Tsao S.T., Yang A.J., Huang C.T., Huang K.C., Lin W.W., HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation, J Leukoc Biol, 2013, 93, 289-299. CrossrefGoogle Scholar

  • [155] Li X., Zhang Y., Xia M., Gulbins E., Boini K.M., Li P.L., Activation of Nlrp3 inflammasomes enhances macrophage lipid-deposition and migration: implication of a novel role of inflammasome in atherogenesis, PLoS One, 2014, 9, e87552. CrossrefGoogle Scholar

  • [156] Stary H.C., Chandler A.B., Dinsmore R.E., Fuster V., Glagov S., Insull W., Jr., Rosenfeld M.E., Schwartz C.J., Wagner W.D., Wissler R.W., A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association, Circulation, 1995, 92, 1355-1374. Google Scholar

  • [157] Buday A., Orsy P., Godo M., Mozes M., Kokeny G., Lacza Z., Koller A., Ungvari Z., Gross M.L., Benyo Z., et al., Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice, Am J Physiol Heart Circ Physiol, 2010, 299, H386-395. Google Scholar

  • [158] Keeley E.C., Mehrad B., Janardhanan R., Salerno M., Hunter J.R., Burdick M.M., Field J.J., Strieter R.M., Kramer C.M., Elevated circulating fibrocyte levels in patients with hypertensive heart disease, J Hypertens, 2012, 30, 1856-1861. CrossrefGoogle Scholar

  • [159] Keeley E.C., Mehrad B., Strieter R.M., The role of fibrocytes in fibrotic diseases of the lungs and heart, Fibrogenesis Tissue Repair, 2011, 4, 2. Google Scholar

  • [160] Soehnlein O., Multiple roles for neutrophils in atherosclerosis, Circ Res, 2012, 110, 875-888. CrossrefGoogle Scholar

  • [161] Sun Z., Atherosclerosis and Atheroma Plaque Rupture: Normal Anatomy of Vasa Vasorum and Their Role Associated with Atherosclerosis, ScientificWorldJournal, 2014, 2014, 285058. Google Scholar

  • [162] Kyriakakis E., Cavallari M., Andert J., Philippova M., Koella C., Bochkov V., Erne P., Wilson S.B., Mori L., Biedermann B.C., et al., Invariant natural killer T cells: linking inflammation and neovascularization in human atherosclerosis, Eur J Immunol, 2010, 40, 3268-3279. CrossrefGoogle Scholar

  • [163] Major A.S., Singh R.R., Joyce S., Van Kaer L., The role of invariant natural killer T cells in lupus and atherogenesis, Immunol Res, 2006, 34, 49-66. CrossrefGoogle Scholar

  • [164] Abedin M., Tintut Y., Demer L.L., Vascular calcification: mechanisms and clinical ramifications, Arterioscler Thromb Vasc Biol, 2004, 24, 1161-1170. CrossrefGoogle Scholar

  • [165] Liberman M., Pesaro A.E., Carmo L.S., Serrano Jr C.V., Vascular calcification: pathophysiology and clinical implications, Einstein (Sao Paulo), 2013, 11, 376-382. Google Scholar

  • [166] Swedenborg J., Mayranpaa M.I., Kovanen P.T., Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms, Arterioscler Thromb Vasc Biol, 2011, 31, 734-740. CrossrefGoogle Scholar

  • [167] Hamers A.A., Hanna R.N., Nowyhed H., Hedrick C.C., de Vries C.J., NR4A nuclear receptors in immunity and atherosclerosis, Curr Opin Lipidol, 2013, 24, 381-385. Google Scholar

  • [168] Boyle J.J., Harrington H.A., Piper E., Elderfield K., Stark J., Landis R.C., Haskard D.O., Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype, Am J Pathol, 2009, 174, 1097-1108. CrossrefGoogle Scholar

  • [169] Sierra-Filardi E., Vega M.A., Sanchez-Mateos P., Corbi A.L., Puig-Kroger A., Heme Oxygenase-1 expression in M-CSFpolarized M2 macrophages contributes to LPS-induced IL-10 release, Immunobiology, 2010, 215, 788-795. Google Scholar

  • [170] Gleissner C.A., Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis, Front Physiol, 2012, 3, 1. Google Scholar

  • [171] Kapourchali F.R., Surendiran G., Chen L., Uitz E., Bahadori B., Moghadasian M.H., Animal models of atherosclerosis, World J Clin Cases, 2014, 2, 126-132. CrossrefGoogle Scholar

About the article

Received: 2013-11-01

Accepted: 2014-07-15

Published Online: 2014-10-10

Citation Information: Inflammasome, ISSN (Online) 2300-102X, DOI: https://doi.org/10.2478/infl-2014-0006.

Export Citation

© 2014 Maria Teresa Montero-Vega. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Comments (0)

Please log in or register to comment.
Log in