Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.
Modified lipoproteins and cholesterol crystals accumulate in the arterial intima and induce foam cell formation and inflammation.
Defective efferocytosis of apoptotic foam cells leads to necrotic core formation.
Defective efferocytosis is a sign of failure in the resolution of inflammation.
Inflammation resolution is mediated by specialized pro-resolving lipid mediators, proteins and signalling gases.
Improvement of the balance between pro-inflammatory and pro-resolving processes enables the resolution of inflammation.
Pro-resolving mediator therapy could be a novel approach to suppressing the formation of clinically dangerous atherosclerotic lesions.
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Williams, K. J. & Tabas, I. The response-to-retention hypothesis of early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 15, 551–561 (1995).
Williams, K. J. & Tabas, I. The response-to-retention hypothesis of atherogenesis reinforced. Curr. Opin. Lipidol. 9, 471–474 (1998).
Tabas, I., Williams, K. J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844 (2007).
Galkina, E. & Ley, K. Immune and inflammatory mechanisms of atherosclerosis*. Annu. Rev. Immunol. 27, 165–197 (2009).
Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).
Hansson, G. K., Libby, P. & Tabas, I. Inflammation and plaque vulnerability. J. Intern. Med. 278, 483–493 (2015).
Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).
Shi, G. P., Bot, I. & Kovanen, P. T. Mast cells in human and experimental cardiometabolic diseases. Nat. Rev. Cardiol. 12, 643–658 (2015).
Zernecke, A. Dendritic cells in atherosclerosis: evidence in mice and humans. Arterioscler. Thromb. Vasc. Biol. 35, 763–770 (2015).
Paulson, K. E. et al. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 106, 383–390 (2010).
Major, A. S., Fazio, S. & Linton, M. F. B-Lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 22, 1892–1898 (2002).
Douna, H. & Kuiper, J. Novel B cell subsets in atherosclerosis. Curr. Opin. Lipidol 27, 493–498 (2016).
Ketelhuth, D. F. J. & Hansson, G. K. Adaptive response of T and B cells in atherosclerosis. Circ. Res. 118, 668–678 (2016).
Doring, Y., Soehnlein, O. & Weber, C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ. Res. 120, 736–743 (2017).
Niccoli, G., Montone, R. A., Sabato, V. & Crea, F. Role of allergic inflammatory cells in coronary artery disease. Circulation 138, 1736–1748 (2018).
Pentikäinen, M. O., Öörni, K., Ala-Korpela, M. & Kovanen, P. T. Modified LDL - trigger of atherosclerosis and inflammation in the arterial intima. J. Intern. Med. 247, 359–370 (2000).
Napoli, C. et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J. Clin. Invest. 100, 2680–2690 (1997).
Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).
Berg, K. E. et al. Elevated CD14++CD16− monocytes predict cardiovascular events. Circ. Cardiovasc. Genet. 5, 122–131 (2012).
Schiopu, A. et al. Associations between macrophage colony-stimulating factor and monocyte chemotactic protein 1 in plasma and first-time coronary events: a nested case-control study. J. Am. Heart Assoc. 5, e002851 (2016).
Brown, M. S. & Goldstein, J. L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu. Rev. Biochem. 52, 223–261 (1983).
Sorci-Thomas, M. G. & Thomas, M. J. Microdomains, inflammation, and atherosclerosis. Circ. Res. 118, 679–691 (2016).
Li, A. C. & Glass, C. K. The macrophage foam cell as a target for therapeutic intervention. Nat. Med. 8, 1235–1242 (2002).
Brown, M. S., Ho, Y. K. & Goldstein, J. L. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. J. Biol. Chem. 255, 9344–9352 (1980).
Öörni, K. et al. Acidification of the intimal fluid: the perfect storm for atherogenesis. J. Lipid Res. 56, 203–214 (2015).
Tabas, I. & Bornfeldt, K. E. Macrophage phenotype and function in different stages of atherosclerosis. Circ. Res. 118, 653–667 (2016).
Serhan, C. N. et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 21, 325–332 (2007).
Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).
Serhan, C. N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am. J. Pathol. 177, 1576–1591 (2010).
Perretti, M. & D’Acquisto, F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat. Rev. Immunol. 9, 62–70 (2009).
Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10, 36–46 (2010).
Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N. & Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 22, 3595–3606 (2008).
Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).
Kolodgie, F. D. et al. Pathologic assessment of the vulnerable human coronary plaque. Heart 90, 1385–1391 (2004).
Kojima, Y., Weissman, I. L. & Leeper, N. J. The role of efferocytosis in atherosclerosis. Circulation 135, 476–489 (2017).
Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016).
Thul, S., Labat, C., Temmar, M., Benetos, A. & Back, M. Low salivary resolvin D1 to leukotriene B4 ratio predicts carotid intima media thickness: a novel biomarker of non-resolving vascular inflammation. Eur. J. Prev. Cardiol. 24, 903–906 (2017).
Viola, J. R. et al. Resolving lipid mediators maresin 1 and resolvin D2 prevent atheroprogression in mice. Circ. Res. 119, 1030–1038 (2016).
Packard, C. J. LDL cholesterol: how low to go? Trends Cardiovasc. Med. 28, 348–354 (2018).
Weber, C. & von Hundelshausen, P. CANTOS Trial validates the inflammatory pathogenesis of atherosclerosis: setting the stage for a new chapter in therapeutic targeting. Circ. Res. 121, 1119–1121 (2017).
Nordestgaard, B. G., Wootton, R. & Lewis, B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler. Thromb. Vasc. Biol. 15, 534–542 (1995).
Shaikh, M. et al. Quantitative studies of transfer in vivo of low density, Sf 12–60, and Sf 60–400 lipoproteins between plasma and arterial intima in humans. Arterioscler. Thromb. 11, 569–577 (1991).
Borén, J. & Williams, K. J. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr. Opin. Lipidol. 27, 473–483 (2016).
Skalen, K. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002).
Smith, E. B., Keen, G. A. & Grant, A. Factors influencing the accumulation in fibrous plaques of lipid derived from low density lipoprotein. I. Relation between fibrin and immobilization of apo B-containing lipoprotein. Atherosclerosis 84, 165–171 (1990).
Öörni, K., Pentikäinen, M. O., Ala-Korpela, M. & Kovanen, P. T. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J. Lipid Res. 41, 1703–1714 (2000).
Houde, M. & Van Eck, M. Escaping the atherogenic trap: preventing LDL fusion and binding in the intima. Atherosclerosis 275, 376–378 (2018).
Soto, Y. et al. Antiatherosclerotic effect of an antibody that binds to extracellular matrix glycosaminoglycans. Arterioscler. Thromb. Vasc. Biol. 32, 595–604 (2012).
Yurdagul, A. Jr., Finney, A. C., Woolard, M. D. & Orr, A. W. The arterial microenvironment: the where and why of atherosclerosis. Biochem. J. 473, 1281–1295 (2016).
Adamson, S. & Leitinger, N. Phenotypic modulation of macrophages in response to plaque lipids. Curr. Opin. Lipidol. 22, 335–342 (2011).
Que, X. et al. Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature 558, 301–306 (2018).
Watson, A. D. et al. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J. Biol. Chem. 272, 13597–13607 (1997).
Fu, P. & Birukov, K. G. Oxidized phospholipids in control of inflammation and endothelial barrier. Transl Res. 153, 166–176 (2009).
Zanoni, I., Tan, Y., Di Gioia, M., Springstead, J. R. & Kagan, J. C. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity 47, 697–709 (2017).
Ruuth, M. et al. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur. Heart J. 39, 2562–2573 (2018).
Lehti, S. et al. Extracellular lipid accumulates in human carotid arteries as distinct three-dimensional structures with proinflammatory properties. Am. J. Pathol. 188, 525–538 (2018).
Guarino, A. J., Tulenko, T. N. & Wrenn, S. P. Cholesterol crystal nucleation from enzymatically modified low-density lipoproteins: combined effect of sphingomyelinase and cholesterol esterase. Biochemistry 43, 1685–1693 (2004).
Rajamäki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLOS ONE 5, e11765 (2010).
Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812–820 (2013).
Westerterp, M. et al. Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 25, 1294–1304 (2017).
Rajamäki, K. et al. P38δ MAPK: a novel regulator of NLRP3 inflammasome activation with increased expression in coronary atherogenesis. Arterioscler. Thromb. Vasc. Biol. 36, 1937–1946 (2016).
van der Heijden, T. et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice - brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1457–1461 (2017).
Patel, M. N. et al. Inflammasome priming in sterile inflammatory disease. Trends Mol. Med. 23, 165–180 (2017).
He, Y., Hara, H. & Nunez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021 (2016).
Kozarov, E. V., Dorn, B. R., Shelburne, C. E., Dunn, W. A. Jr & Progulske-Fox, A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler. Thromb. Vasc. Biol. 25, e17–e18 (2005).
Caesar, R., Fak, F. & Backhed, F. Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. J. Intern. Med. 268, 320–328 (2010).
Lopategi, A. et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol. 105, 25–36 (2018).
Wang, L., Chen, Y., Li, X., Zhang, Y. & Gulbins, E. Enhancement of endothelial permeability by free fatty acid through lysosomal cathepsin B-mediated Nlrp3 inflammasome activation. Oncotarget 7, 73229–73241 (2016).
Schroder, K., Zhou, R. & Tschopp, J. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296–300 (2010).
Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).
Duewell, P. & Latz, E. Assessment and quantification of crystal-induced lysosomal damage. Methods Mol. Biol. 1040, 19–27 (2013).
Grebe, A., Hoss, F. & Latz, E. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ. Res. 122, 1722–1740 (2018).
Westerterp, M. et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis and atherogenesis. Circulation 138, 898–912 (2018).
Rhoads, J. P. et al. Oxidized low-density lipoprotein immune complex priming of the Nlrp3 inflammasome involves TLR and FcγR cooperation and is dependent on CARD9. J. Immunol. 198, 2105–2114 (2017).
Estruch, M. et al. Electronegative LDL induces priming and inflammasome activation leading to IL-1beta release in human monocytes and macrophages. Biochim. Biophys. Acta 1851, 1442–1449 (2015).
Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).
Fredman, G. & Tabas, I. Boosting inflammation resolution in atherosclerosis: the next frontier for therapy. Am. J. Pathol. 187, 1211–1221 (2017).
Mirakaj, V., Dalli, J., Granja, T., Rosenberger, P. & Serhan, C. N. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 211, 1037–1048 (2014).
Proto, J. D. et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 49, 666–677 (2018).
Li, X. et al. Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice. J. Am. Heart Assoc. 4, e001856 (2015).
Breitzig, M., Bhimineni, C., Lockey, R. & Kolliputi, N. 4-hydroxy-2-nonenal: a critical target in oxidative stress? Am. J. Physiol. Cell Physiol. 311, C537–C543 (2016).
Serhan, C. N., Krishnamoorthy, S., Recchiuti, A. & Chiang, N. Novel anti-inflammatory—pro-resolving mediators and their receptors. Curr. Top. Med. Chem. 11, 629–647 (2011).
Radmark, O. & Samuelsson, B. Regulation of 5-lipoxygenase enzyme activity. Biochem. Biophys. Res. Commun. 338, 102–110 (2005).
Fredman, G. et al. Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway. Proc. Natl Acad. Sci. USA 111, 14530–14535 (2014).
Dichlberger, A., Kovanen, P. T. & Schneider, W. J. Mast cells: from lipid droplets to lipid mediators. Clin. Sci. 125, 121–130 (2013).
Werz, O., Klemm, J., Samuelsson, B. & Radmark, O. 5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc. Natl Acad. Sci. USA 97, 5261–5266 (2000).
Cai, B. et al. MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc. Natl Acad. Sci. USA 113, 6526–6531 (2016).
Cai, B. et al. MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci. Signal. 11, eaar3721 (2018).
Dinarello, C. A. Interleukin-1β and the autoinflammatory diseases. N. Engl. J. Med. 360, 2467–2470 (2009).
D’Elia, R. V., Harrison, K., Oyston, P. C., Lukaszewski, R. A. & Clark, G. C. Targeting the “cytokine storm” for therapeutic benefit. Clin. Vaccine Immunol. 20, 319–327 (2013).
English, J. T., Norris, P. C., Hodges, R. R., Dartt, D. A. & Serhan, C. N. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot. Essent. Fatty Acids 117, 17–27 (2017).
Arnardottir, H., Orr, S. K., Dalli, J. & Serhan, C. N. Human milk proresolving mediators stimulate resolution of acute inflammation. Mucosal Immunol. 9, 757–766 (2016).
Kasikara, C., Doran, A. C., Cai, B. & Tabas, I. The role of non-resolving inflammation in atherosclerosis. J. Clin. Invest. 128, 2713–2723 (2018).
Wallace, J. L., Vong, L., McKnight, W., Dicay, M. & Martin, G. R. Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats. Gastroenterology 137, 569–578 (2009).
Han, X. & Boisvert, W. A. Interleukin-10 protects against atherosclerosis by modulating multiple atherogenic macrophage function. Thromb. Haemost. 113, 505–512 (2015).
de Jong, R. J. et al. Protective aptitude of annexin A1 in arterial neointima formation in atherosclerosis-prone mice - brief report. Arterioscler. Thromb. Vasc. Biol. 37, 312–315 (2017).
Zhang, R. et al. Hydrogen sulfide inhibits L-type calcium currents depending upon the protein sulfhydryl state in rat cardiomyocytes. PLOS ONE 7, e37073 (2012).
Mani, S. et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 127, 2523–2534 (2013).
Petri, M. H. et al. Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E−/− mice. Br. J. Pharmacol. 174, 4043–4054 (2017).
Krishnamoorthy, N. et al. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J. Immunol. 194, 863–867 (2015).
Foks, A. C., Lichtman, A. H. & Kuiper, J. Treating atherosclerosis with regulatory T cells. Arterioscler. Thromb. Vasc. Biol. 35, 280–287 (2015).
Perretti, M., Leroy, X., Bland, E. J. & Montero-Melendez, T. Resolution pharmacology: opportunities for therapeutic innovation in inflammation. Trends Pharmacol. Sci. 36, 737–755 (2015).
Bäck, M. et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR review 7. Br. J. Pharmacol. 171, 3551–3574 (2014).
Petri, M. H. et al. The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability. Cardiovasc. Res. 105, 65–74 (2015).
Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018).
Kostopoulos, C. G., Spiroglou, S. G., Varakis, J. N., Apostolakis, E. & Papadaki, H. H. Chemerin and CMKLR1 expression in human arteries and periadventitial fat: a possible role for local chemerin in atherosclerosis? BMC Cardiovasc. Disord. 14, 56 (2014).
Ho, K. J. et al. Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am. J. Pathol. 177, 2116–2123 (2010).
Drechsler, M. et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ. Res. 116, 827–835 (2015).
Fredman, G. et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl Med. 7, 275ra220 (2015).
Petri, M. H. et al. Aspirin-triggered 15-epi-lipoxin A4 signals through FPR2/ALX in vascular smooth muscle cells and protects against intimal hyperplasia after carotid ligation. Int. J. Cardiol. 179, 370–372 (2015).
Akagi, D., Chen, M., Toy, R., Chatterjee, A. & Conte, M. S. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. FASEB J. 29, 2504–2513 (2015).
Miyahara, T. et al. D-Series resolvin attenuates vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury. FASEB J. 27, 2220–2232 (2013).
El Kebir, D., Gjorstrup, P. & Filep, J. G. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc. Natl Acad. Sci. USA 109, 14983–14988 (2012).
Herova, M., Schmid, M., Gemperle, C. & Hersberger, M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J. Immunol. 194, 2330–2337 (2015).
Ohira, T. et al. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J. Biol. Chem. 285, 3451–3461 (2010).
Kennedy, A. J. & Davenport, A. P. International Union of Basic and Clinical Pharmacology CIII: chemerin receptors CMKLR1 (chemerin1) and GPR1 (chemerin2) nomenclature, pharmacology, and function. Pharmacol. Rev. 70, 174–196 (2018).
Lopez-Vicario, C. et al. Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals. Sci. Rep. 7, 15724 (2017).
Hasturk, H. et al. Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler. Thromb. Vasc. Biol. 35, 1123–1133 (2015).
Salic, K. et al. Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin. Atherosclerosis 250, 158–165 (2016).
Neves, K. B. et al. Chemerin regulates crosstalk between adipocytes and vascular cells through Nox. Hypertension 66, 657–666 (2015).
Kunimoto, H. et al. Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure. Am. J. Physiol. Heart Circ. Physiol. 309, H1017–H1028 (2015).
Aung, T. et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 3, 225–234 (2018).
The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med. 379, 1540–1550 (2018).
Bhatt, D. L. et al. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin. Cardiol. 40, 138–148 (2017).
Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).
Elajami, T. K. et al. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J. 30, 2792–2801 (2016).
Skarke, C. et al. Bioactive products formed in humans from fish oils. J. Lipid Res. 56, 1808–1820 (2015).
Gromovsky, A. D. et al. Delta-5 fatty acid desaturase FADS1 impacts metabolic disease by balancing proinflammatory and proresolving lipid mediators. Arterioscler. Thromb. Vasc. Biol. 38, 218–231 (2018).
Tuomisto, T. T. et al. Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2. Cardiovasc. Res. 78, 175–184 (2008).
Wallace, J. L., Ianaro, A., Flannigan, K. L. & Cirino, G. Gaseous mediators in resolution of inflammation. Semin. Immunol. 27, 227–233 (2015).
Dufton, N., Natividad, J., Verdu, E. F. & Wallace, J. L. Hydrogen sulfide and resolution of acute inflammation: a comparative study utilizing a novel fluorescent probe. Sci. Rep. 2, 499 (2012).
Wang, Y. et al. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 173–179 (2009).
Chiang, N. et al. Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits. J. Immunol. 190, 6378–6388 (2013).
Winkels, H., Ehinger, E., Ghosheh, Y., Wolf, D. & Ley, K. Atherosclerosis in the single-cell era. Curr. Opin. Lipidol 29, 389–396 (2018).
Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018).
Shibata, N. et al. 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages. J. Biol. Chem. 288, 35812–35823 (2013).
Talbot, C. P. J., Plat, J., Ritsch, A. & Mensink, R. P. Determinants of cholesterol efflux capacity in humans. Prog. Lipid Res. 69, 21–32 (2018).
van Gils, J. M. et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat. Immunol. 13, 136–143 (2012).
Swirski, F. K. et al. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc. Natl Acad. Sci. USA 103, 10340–10345 (2006).
Williams, J. W. et al. Limited macrophage positional dynamics in progressing or regressing murine atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 38, 1702–1710 (2018).
Nagenborg, J., Goossens, P., Biessen, E. A. L. & Donners, M. Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment. Eur. J. Pharmacol. 816, 14–24 (2017).
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 129, 1551–1559 (2014).
Bennett, M. R., Sinha, S. & Owens, G. K. Vascular smooth muscle cells in atherosclerosis. Circ. Res. 118, 692–702 (2016).
Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).
Ensan, S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159–168 (2016).
Quintar, A. et al. Endothelial protective monocyte patrolling in large arteries intensified by western diet and atherosclerosis. Circ. Res. 120, 1789–1799 (2017).
Patel, A. A. et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J. Exp. Med. 214, 1913–1923 (2017).
Gautier, E. L., Jakubzick, C. & Randolph, G. J. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1412–1418 (2009).
Di Gregoli, K. & Johnson, J. L. Role of colony-stimulating factors in atherosclerosis. Curr. Opin. Lipidol. 23, 412–421 (2012).
Ushach, I. & Zlotnik, A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J. Leukoc. Biol. 100, 481–489 (2016).
da Silva, R. F., Lappalainen, J., Lee-Rueckert, M. & Kovanen, P. T. Conversion of human M-CSF macrophages into foam cells reduces their proinflammatory responses to classical M1-polarizing activation. Atherosclerosis 248, 170–178 (2016).
Kim, K. et al. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ. Res. 123, 1127–1142 (2018).
Colin, S., Chinetti-Gbaguidi, G. & Staels, B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 262, 153–166 (2014).
Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).
Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).
Italiani, P. & Boraschi, D. From monocytes to M1/M2 macrophages: phenotypical versus functional differentiation. Front. Immunol. 5, 514 (2014).
Chinetti-Gbaguidi, G. et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ. Res. 108, 985–995 (2011).
de Jong, R., Leoni, G., Drechsler, M. & Soehnlein, O. The advantageous role of annexin A1 in cardiovascular disease. Cell Adh. Migr. 11, 261–274 (2017).
Li, Y. et al. Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2. Oncogene 30, 3887–3899 (2011).
Titos, E. et al. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J. Immunol. 187, 5408–5418 (2011).
Dalli, J. & Serhan, C. Macrophage proresolving mediators — the when and where. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MCHD-0001-2014 (2016).
Cai, B. et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J. Clin. Invest. 127, 564–568 (2017).
Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).
Gordon, D., Reidy, M. A., Benditt, E. P. & Schwartz, S. M. Cell proliferation in human coronary arteries. Proc. Natl Acad. Sci. USA 87, 4600–4604 (1990).
Kavurma, M. M., Rayner, K. J. & Karunakaran, D. The walking dead: macrophage inflammation and death in atherosclerosis. Curr. Opin. Lipidol. 28, 91–98 (2017).
Tait, S. W., Ichim, G. & Green, D. R. Die another way — non-apoptotic mechanisms of cell death. J. Cell Sci. 127, 2135–2144 (2014).
Das, G., Shravage, B. V. & Baehrecke, E. H. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb. Perspect. Biol. 4, a008813 (2012).
Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13, 655–667 (2011).
Karunakaran, D. et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci. Adv. 2, e1600224 (2016).
Andres, V., Pello, O. M. & Silvestre-Roig, C. Macrophage proliferation and apoptosis in atherosclerosis. Curr. Opin. Lipidol. 23, 429–438 (2012).
Mai, J. et al. The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway. Atherosclerosis 278, 259–268 (2018).
Prieto, P. et al. Activation of autophagy in macrophages by pro-resolving lipid mediators. Autophagy 11, 1729–1744 (2015).
Crisby, M. et al. Cell death in human atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis 130, 17–27 (1997).
Crisby, M. et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 103, 926–933 (2001).
Han, C. Z. & Ravichandran, K. S. Metabolic connections during apoptotic cell engulfment. Cell 147, 1442–1445 (2011).
Hamada, M. et al. MafB promotes atherosclerosis by inhibiting foam-cell apoptosis. Nat. Commun. 5, 3147 (2014).
Yurdagul, A. et al. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86 (2017).
Penaloza, C., Lin, L., Lockshin, R. A. & Zakeri, Z. Cell death in development: shaping the embryo. Histochem. Cell Biol. 126, 149–158 (2006).
Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).
Elliott, M. R. & Ravichandran, K. S. The dynamics of apoptotic cell clearance. Dev. Cell 38, 147–160 (2016).
Krishnamoorthy, S., Recchiuti, A., Chiang, N., Fredman, G. & Serhan, C. N. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am. J. Pathol. 180, 2018–2027 (2012).
Godson, C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).
Mitchell, S. et al. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J. Am. Soc. Nephrol. 13, 2497–2507 (2002).
Campana, L. et al. The STAT3-IL-10-IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J. Immunol. 200, 1169–1187 (2018).
Ogden, C. A. et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt’s lymphoma. J. Immunol. 174, 3015–3023 (2005).
Cardilo-Reis, L. et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol. Med. 4, 1072–1086 (2012).
Green, D. R., Oguin, T. H. & Martinez, J. The clearance of dying cells: table for two. Cell Death Differ. 23, 915–926 (2016).
Thorp, E. & Tabas, I. Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J. Leukoc. Biol. 86, 1089–1095 (2009).
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. 41, 2515–2518 (2011).
Tajbakhsh, A., Rezaee, M., Kovanen, P. T. & Sahebkar, A. Efferocytosis in atherosclerotic lesions: malfunctioning regulatory pathways and control mechanisms. Pharmacol. Ther. 188, 12–25 (2018).
Tabas, I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ. Res. 107, 839–850 (2010).
Tabas, I. Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. Antioxid. Redox Signal. 11, 2333–2339 (2009).
Vengrenyuk, Y. et al. Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 535–546 (2015).
Penberthy, K. K. & Ravichandran, K. S. Apoptotic cell recognition receptors and scavenger receptors. Immunol. Rev. 269, 44–59 (2016).
Thorp, E. et al. Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK). J. Biol. Chem. 286, 33335–33344 (2011).
Thorp, E., Cui, D., Schrijvers, D. M., Kuriakose, G. & Tabas, I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe−/− mice. Arterioscler. Thromb. Vasc. Biol. 28, 1421–1428 (2008).
Ait-Oufella, H. et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 1429–1431 (2008).
Gorovoy, M., Gaultier, A., Campana, W. M., Firestein, G. S. & Gonias, S. L. Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages. J. Leukoc. Biol. 88, 769–778 (2010).
Yancey, P. G. et al. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler. Thromb. Vasc. Biol. 30, 787–795 (2010).
Overton, C. D., Yancey, P. G., Major, A. S., Linton, M. F. & Fazio, S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ. Res. 100, 670–677 (2007).
Foks, A. C. et al. Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 36, 456–465 (2016).
Tao, H. et al. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res. 56, 1449–1460 (2015).
Kojima, Y. et al. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J. Clin. Invest. 124, 1083–1097 (2014).
Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).
McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).
Nanda, V. et al. CDKN2B regulates TGFβ signaling and smooth muscle cell investment of hypoxic neovessels. Circ. Res. 118, 230–240 (2016).
Kojima, Y. et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536, 86–90 (2016).
Tsai, R. K. & Discher, D. E. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).
Feig, J. E. et al. Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLOS ONE 7, e39790 (2012).
Tang, X. et al. The effect of statin therapy on plaque regression following acute coronary syndrome: a meta-analysis of prospective trials. Coron. Artery Dis. 27, 636–649 (2016).
Rosenson, R. S., Hegele, R. A., Fazio, S. & Cannon, C. P. The evolving future of PCSK9 inhibitors. J. Am. Coll. Cardiol. 72, 314–329 (2018).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Dalli, J. & Serhan, C. N. Identification and structure elucidation of the pro-resolving mediators provides novel leads for resolution pharmacology. Br. J. Pharmacol. https://doi.org/10.1111/bph.14336 (2018).
Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012).
Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009).
Romano, M., Cianci, E., Simiele, F. & Recchiuti, A. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. Eur. J. Pharmacol. 760, 49–63 (2015).
Pope, N. H. et al. D-Series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization. FASEB J. 30, 4192–4201 (2016).
Petri, M. H. et al. Resolution of inflammation through the lipoxin and ALX/FPR2 receptor pathway protects against abdominal aortic aneurysms. JACC Basic Transl Sci. 3, 719–727 (2018).
Liu, G. et al. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration. FASEB J. 32, 5413–5425 (2018).
M.B.’s research is supported by grants from the Swedish Research Council (2014–2312), the Swedish Heart and Lung Foundation (20180571) and the Marianne and Marcus Wallenberg Foundation (2015.0104). A.Y.’s research is supported by the NIH (T32 HL007343-28 and K99 HL145131). I.T.’s research is supported by the NIH (R01 HL075662, R01 HL127464 and R01 HL132412). K.Ö.’s research is supported by the Academy of Finland (315568), the Aarne Koskelo Foundation and the Finnish Foundation for Cardiovascular Research. The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.
Nature Reviews Cardiology thanks C. J. Binder, K. Ley, and the other anonymous reviewer(s), for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Bäck, M., Yurdagul, A., Tabas, I. et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 16, 389–406 (2019). https://doi.org/10.1038/s41569-019-0169-2
Atorvastatin inhibits pyroptosis through the lncRNA NEXN-AS1/NEXN pathway in human vascular endothelial cells
Fargesin alleviates atherosclerosis by promoting reverse cholesterol transport and reducing inflammatory response
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (2020)
SNHG1 Inhibits ox-LDL-Induced Inflammatory Response and Apoptosis of HUVECs via Up-Regulating GNAI2 and PCBP1
Frontiers in Pharmacology (2020)
High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation
Metabolic Syndrome and Related Disorders (2020)
Nature Reviews Immunology (2020)