Inflammation and Atherosclerosis: Current Pathogenesis
Abstract
BACKGROUND: The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown.
CONTENT: Chronic inflammation is recognized as a major driving force in atherogenesis. The sites of atherosclerotic plaque development in the arterial wall are characterized by cholesterol accumulation and infiltration of peripheral blood monocytes, which gradually differentiate into macrophages. Cholesterol crystals, the common constituents of atherosclerotic lesions, include NLRP3 inflammasome activation and IL-1β secretion in human macrophages, promote an inflammatory milieu and thus drive lesion progression. Consequently, the cholesterol crystal-induced inflammasome activation may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
SUMMARY: The crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions. This finding provides new insights into the pathogenesis of atherosclerosis and indicates new potential molecular targets for the therapy of this disease.
KEYWORDS: atherosclerosis, inflammation, neutrophil, macrophages, inflammasome, cholesterol crystal
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Libby P, Ridker PM, Hannsson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011; 473: 317-24, CrossRef.
Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med. 2011; 17: 1410-22, CrossRef.
Steinberg D. The cholesterol wars: the skeptic vs the preponderance of evidence. 1st ed. San Diego: Academic Press; 2007, NLMID.
Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005; 46: 1225-28, CrossRef.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350: 1495-504, CrossRef.
Rye KA, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res. 2009; 50: S195-200. CrossRef.
Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007; 117: 746-56, CrossRef.
Libby P, Ridker PM. Inflammation and atherothrombosis. J Am Coll Cardiol. 2006; 48: 33-46, CrossRef.
Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006; 116: 4-15, CrossRef.
Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessos from mouse models. Nat Rev Immunol. 2008; 8: 802-15, CrossRef.
Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation. 2010; 122: 1837-45, CrossRef.
Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011; 145: 341-55, CrossRef.
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464: 1357-61, CrossRef.
Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE. 2010; 5: e11765, CrossRef.
Majno G. The healing hand; man and wound in the ancient world. Cambridge: Harvard University Press; 1975, NLMID.
Coggins M, Rosenzweig A. The fire within: Cardiac inflammatory signaling in health and disease. Circ Res. 2012; 110: 116-25, CrossRef.
Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol. 2009; 27: 165-97, CrossRef.
Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2001; 81: 1-5, CrossRef.
Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994; 12: 991-1045, CrossRef.
Lundberg AM, Yan ZQ. Innate immune recognition receptors and damage-associated molecular patterns in plaque inflammation. Curr Opin Lipidol. 2011; 22: 343-49, CrossRef.
Fredrikson GN, Hedblad B, Berglund G, Alm R, Ares M, Cercek B, et al. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003; 23: 872-8, CrossRef.
Simon DI, Zidar D. Neutrophils in atherosclerosis: Alarmin evidence of a hit and run? Circ Res. 2012; 110: 1036-8, CrossRef.
Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011; 12: 204-12, CrossRef.
Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012; 110: 875-88, CrossRef.
Rotzius P, Thams S, Soehnlein O, Kenne E, Tseng CN, Björkstro ̈m NK, et al. Distinct infiltration of neutrophils in lesion shoulders in ApoE/mice. Am J Pathol. 2010; 177: 493-500, CrossRef.
Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Bidzhekov K, Meiler S, et al. Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res. 2008; 102: 209-17, CrossRef.
Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010; 33: 657-70, CrossRef.
Borregaard N, Sørensen OE, Theilgaard-Monch K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol. 2007; 28: 340-5, CrossRef.
Borregaard N, Cowland JB. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood. 1997; 89: 3503-21, PMID.
Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol. 2010; 10: 427-39, CrossRef.
Yang D, de la Rosa G, Tewary P, Oppenheim JJ. Alarmins link neutrophils and dendritic cells. Trends Immunol. 2009; 30: 531-7, CrossRef.
Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H, et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood. 2008; 112: 1461-71, CrossRef.
van der Does AM, Beekhuizen H, Ravensbergen B, Vos T, Ottenhoff TH, van Dissel JT, et al. LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature. J Immunol. 2010; 185: 1442-9, CrossRef.
Lee TD, Gonzalez ML, Kumar P, Chary-Reddy S, Grammas P, Pereira HA. CAP37, a novel inflammatory mediator: its expression in endothelial cells and localization to atherosclerotic lesions. Am J Pathol. 2002; 160: 841-8, CrossRef.
Edfeldt K, Agerberth B, Rottenberg ME, Gudmundsson GH, Wang XB, Mandal K, et al. Involvement of the antimicrobial peptide LL-37 in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2006; 26: 1551-7, CrossRef.
Barnathan ES, Raghunath PN, Tomaszewski JE, Ganz T, Cines DB, Higazi A al-R. Immunohistochemical localization of defensin in human coronary vessels. Am J Pathol. 1997; 150: 1009-20, PMID.
Hemdahl AL, Gabrielsen A, Zhu C, Eriksson P, Hedin U, Kastrup J, et al. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol. 2006; 26: 136-42, CrossRef.
Pereira HA, Moore P, Grammas P. CAP37, a neutrophil granulederived protein stimulates protein kinase C activity in endothelial cells. J Leukoc Biol. 1996; 60: 415-22, PMID.
Lee TD, Gonzalez ML, Kumar P, Grammas P, Pereira HA. CAP37, a neutrophil-derived inflammatory mediator, augments leukocyte adhesion to endothelial monolayers. Microvasc Res. 2003; 66: 38-48, CrossRef.
Taekema-Roelvink ME, Kooten C, Kooij SV, Heemskerk E, Daha MR. Proteinase 3 enhances endothelial monocyte chemoattractant protein-1 production and induces increased adhesion of neutrophils to endothelial cells by upregulating intercellular cell adhesion molecule-1. J Am Soc Nephrol. 2001; 12: 932-40, PMID.
Chaly YV, Paleolog EM, Kolesnikova TS, Tikhonov II, Petratchenko EV, Voitenok NN. Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw. 2000;11: 257-266, PMID.
Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Chen C. Neutrophil antimicrobial peptide alpha-defensin causes endothelial dysfunction in porcine coronary arteries. J Vasc Surg. 2006; 43: 357-63, CrossRef.
Zhang J, Alcaide P, Liu L, Sun J, He A, Luscinskas FW, et al. Regulation of endothelial cell adhesion molecule expression by mast cells, macrophages, and neutrophils. PLoS One. 2011; 6: e14525, CrossRef.
van Leeuwen M, Gijbels MJ, Duijvestijn A, Smook M, van de Gaar MJ, Heeringa P, et al. Accumulation of myeloperoxidasepositive neutrophils in atherosclerotic lesions in LDLR-/- mice. Arterioscler Thromb Vasc Biol. 2008; 28: 84-89, CrossRef.
Baetta R, Corsini A. Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis. 2010; 210: 1-13, CrossRef.
Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidasegeneratedreactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest. 1999; 103: 1547-60, CrossRef.
Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, et al. Peripheral blood concentrations of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol. 1998; 32: 368-72, CrossRef.
Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat Med. 2011, 11: 1381-90, CrossRef.
Swirski FK, Weissleder R, Pittet MJ. Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009, 29: 1424-32, CrossRef.
Ley K, Miller YI, Hedrick CC. Mpnocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol. 2011, 31: 1506-16, CrossRef.
Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001, 104: 503-16, CrossRef.
Mestas J, Ley K. Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med. 2008, 18: 228-32, CrossRef.
Johnson JL, Newby AC. Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol. 2009, 20: 370-8, CrossRef.
Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res. 2010; 106: 383-90, CrossRef.
Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003; 3:23-35, CrossRef.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002; 23: 549-55, CrossRef.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8: 958-69, CrossRef.
Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009; 9: 259-70, CrossRef.
Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13: 453-61, CrossRef.
Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009; 27: 669-92, CrossRef.
Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis. A question balance. Arterioscler Thromb vasc Biol. 2009; 29: 1419-23, CrossRef.
Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, et al. 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. 2002; 277: 49982-8, CrossRef.
Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM et al. Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005; 15: 2192-201, CrossRef.
Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, Alvarez-Leite JI, et al. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2009; 29: 19-26, CrossRef.
Tabas I, Li Y, Brocia RW, Xu SW, Swenson TL, Williams KJ. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. J Biol Chem. 1993; 268: 20419-32, PMID.
Kruth HS, Jones NL, Huang W, Zhao B, Ishii I, Chang J, et al. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem. 2005; 280: 2352-60, CrossRef.
Maxfield FR, Tabas, I. Role of cholesterol and lipid organization in disease. Nature. 2005; 438: 612-21, CrossRef.
Tarr PT, Edwards PA. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res. 2008; 49: 169-82, CrossRef.
Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab 2008, 7: 365-75, CrossRef.
Rothblat GH, Philips MC. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr Opin Lipidol 2010, 21: 229-38, CrossRef.
Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868-74, CrossRef.
Galkina E, Ley K. Leukocyte influx in atherosclerosis. Curr Drug Targets. 2007; 8: 1239-48, CrossRef.
Shibata N, Glass GK. Regulation of macrophage function in inflammation and atherosclerosis. J Lipid Res 2009; 50: S277-81, CrossRef.
Adamson S, Leitinger N. Phenotypic modulation of macrophages in response to plaque lipids. Curr Opin Lipidol. 2011; 22: 335-42, CrossRef.
Waldo SW, Li Y, Buono C, Zhao B, Billings EM, Chang J, et al. Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Pathol. 2008; 172: 1112-26, CrossRef.
Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with antiinflammatory properties. Cell Metab. 2007; 6: 137-43, CrossRef.
Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, R, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res. 2010; 107: 737-46, CrossRef.
Rath E, Haller D. Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies. Eur J Nutr. 2011; 50: 219-33, CrossRef.
Zhang K. Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Int J Clin Exp Med. 2010; 3: 33-40, PMID.
Kitamura M. Control of NF-κB and inflammation by the unfolded protein response. Int Rev Immunol. 2011; 30: 4-15, CrossRef.
Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140: 900-27, CrossRef.
Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006; 124: 587-99, CrossRef.
Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008; 454: 455-62, CrossRef.
Gotoh T, Endo M, Oike Y. Endoplasmic reticulum stress-related inflammation and cardiovascular diseases. Int J Inflam. 2011; 2011: 259462, CrossRef.
Tabas I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res. 2010; 107: 839-50, CrossRef.
Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009, 27: 229-65, CrossRef.
Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296: 301-5, CrossRef.
Seong SY, Matzinger P. Hydrophobicity: an ancient damagea-ssociated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004; 4: 469-78, CrossRef.
Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, et al. 2001. Genomic DNA released by dying cells induces the maturation of APCs. J Immunol. 2001; 167: 2602-7, CrossRef.
Martinon F, Pe ́trilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440: 237-41, CrossRef.
Schroder K, Tschopp J. The inflammasomes. Cell 2010, 140: 821-32, CrossRef.
Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011; 29: 707-35, CrossRef.
Dinarello CA. IL-1: discoveries, controversies and future directions. Eur J Immunol. 2010; 40: 599-606, CrossRef.
Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, van Ness K, Greenstreet TA, et al. Molecular cloning of the interleukin-1β converting enzyme. Science. 1991; 256: 97-100, CrossRef.
Keller M, Rüegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell.2008; 132: 818-31, CrossRef.
Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 2008, 9: 847-56, CrossRef.
Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA. 2008,;105: 9035-40, CrossRef.
Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440: 237-41, CrossRef.
DOI: https://doi.org/10.18585/inabj.v4i2.165
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