Macrophage origin, phenotypic diversity, and modulatory signaling pathways in the atherosclerotic plaque microenvironment

Abstract

Atherosclerosis is the main pathological basis of most cardiovascular diseases and the leading health threat in the world. Of note, lipid-lowering therapy cannot completely retard atherosclerosis progression, even in patients treated with combined statins and PCSK9 inhibitors. This failure further impels researchers to explore other underlying therapeutic strategies except for lipid-lowering. Monocytes and macrophages are the major immune cell groups in atherosclerotic plaques. They play important roles in all stages of atherosclerosis, including the occurrence, advance, and regression. It is interesting that macrophages are demonstrated to have plastic and heterogenous characteristics within the dynamic atherosclerotic plaque microenvironment. Furthermore, the phenotype of macrophages can switch upon different microenvironmental stimulus. Therefore, macrophages have become a potential therapeutic target for anti-atherosclerosis treatment. This article reviews the phenotypic diversity of macrophages and their roles in dynamic atherosclerotic plaque microenvironment, especially the related signaling pathways involved in macrophage polarization and compounds exhibiting therapeutic effects.

Keywords

Atherosclerosis / microenvironment / signaling / polarization / treatment

References

[1] Ross R.Atherosclerosis - an inflammatory disease.N Engl J Med1999;340:115-26

[2] Moore KJ,Fisher EA.Macrophages in atherosclerosis: a dynamic balance.Nat Rev Immunol2013;13:709-21 PMCID:PMC4357520

[3] Tabas I.Macrophage phenotype and function in different stages of atherosclerosis.Circ Res2016;118:653-67 PMCID:PMC4762068

[4] Amengual J.Monocytes and macrophages in atherogenesis.Curr Opin Lipidol2019;30:401-8 PMCID:PMC7809604

[5] Bories GFP.Macrophage metabolism in atherosclerosis.FEBS Lett2017;591:3042-60

[6] Momtazi-Borojeni AA,Nikfar B,Ekhlasi-Hundrieser M.Curcumin as a potential modulator of M1 and M2 macrophages: new insights in atherosclerosis therapy.Heart Fail Rev2019;24:399-409

[7] Smith JD,Ginsberg M,Tian J.Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.Proc Natl Acad Sci U S A1995;92:8264-8 PMCID:PMC41137

[8] Glass CK.Atherosclerosis.Cell2001;104:503-16

[9] Tsaousi A,Di Gregoli K.Plaque size is decreased but M1 macrophage polarization and rupture related metalloproteinase expression are maintained after deleting T-Bet in ApoE null mice.PLoS One2016;11:e0148873 PMCID:PMC4757422

[10] Stöger JL,van der Velden S.Distribution of macrophage polarization markers in human atherosclerosis.Atherosclerosis2012;225:461-8

[11] Cho KY,Kuroda S.The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery.J Stroke Cerebrovasc Dis2013;22:910-8

[12] Shaikh S,Lahiri R,Thies F.Macrophage subtypes in symptomatic carotid artery and femoral artery plaques.Eur J Vasc Endovasc Surg2012;44:491-7

[13] Melendez QM,Wooten CJ.Hypercholesterolemia: The role of PCSK9.Arch Biochem Biophys2017;625-626:39-53

[14] Geissmann F,Littman DR.Blood monocytes consist of two principal subsets with distinct migratory properties.Immunity2003;19:71-82

[15] Gordon S.Monocyte and macrophage heterogeneity.Nat Rev Immunol2005;5:953-64

[16] Kim H.The transcription factor MafB promotes anti-inflammatory M2 polarization and cholesterol efflux in macrophages.Sci Rep2017;7:7591 PMCID:PMC5548719

[17] Solanki S,Birnbaumer L.Reduced necrosis and content of apoptotic M1 macrophages in advanced atherosclerotic plaques of mice with macrophage-specific loss of Trpc3.Sci Rep2017;7:42526 PMCID:PMC5301208

[18] Paul A,Hogan R.Cholesterol acceptors regulate the lipidome of macrophage foam cells.Int J Mol Sci2019;20:3784 PMCID:PMC6695943

[19] Medbury HJ,Guiffre AK,Lam TH.Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes.Int Angiol2008;27:114-23

[20] Bouhlel MA,Rigamonti E.PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.Cell Metab2007;6:137-43

[21] Chistiakov DA,Nikiforov NG,Sobenin IA.Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes.Int J Cardiol2015;184:436-45

[22] Adamson S.Phenotypic modulation of macrophages in response to plaque lipids.Curr Opin Lipidol2011;22:335-42 PMCID:PMC3979355

[23] Nagenborg J,Biessen EAL.Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment.Eur J Pharmacol2017;816:14-24

[24] Guo S,Gu H.Proprotein convertase subtilisin/kexin-type 9 and lipid metabolism.Adv Exp Med Biol2020;1276:137-56

[25] She ZG,Kotamraju VR,Jansen S.Plaque-penetrating peptide inhibits development of hypoxic atherosclerotic plaque.J Control Release2016;238:212-20

[26] Tabas I.Monocyte-macrophages and T cells in atherosclerosis.Immunity2017;47:621-34 PMCID:PMC5747297

[27] Rahman MS,Woollard KJ.Effects of dyslipidaemia on monocyte production and function in cardiovascular disease.Nat Rev Cardiol2017;14:387-400

[28] Mildner A,Jung S.Murine monocytes: origins, subsets, fates, and functions.Microbiol Spectr2016;4

[29] Jia SJ,Zhao M.Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis.Cardiovasc Ther2017;35:e12262

[30] Narasimhan PB,Hamers AAJ.Nonclassical monocytes in health and disease.Annu Rev Immunol2019;37:439-56

[31] Spitzer MH.Mass cytometry: single cells, many features.Cell2016;165:780-91 PMCID:PMC4860251

[32] Xiang GA,Su CC.Dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in a mouse model of experimental silicosis.Inhal Toxicol2016;28:393-402

[33] Hamers AAJ,Thomas GD.Human monocyte heterogeneity as revealed by high-dimensional mass cytometry.Arterioscler Thromb Vasc Biol2019;39:25-36 PMCID:PMC6697379

[34] Villani AC,Reynolds G.Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.Science2017;356:eaah4573 PMCID:PMC5775029

[35] Wildgruber M,Wendorff H.The "Intermediate" CD14⁺⁺CD16⁺ monocyte subset increases in severe peripheral artery disease in humans.Sci Rep2016;6:39483 PMCID:PMC5171878

[36] Saha AK,Dallo SF,Huang TH.Cholesterol regulates monocyte rolling through CD44 distribution.Biophys J2017;112:1481-8 PMCID:PMC5389964

[37] Tolani S,Murphy AJ.Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children.Atherosclerosis2013;229:79-85 PMCID:PMC3691284

[38] Schnitzler JG,Tiessens F.Nile Red Quantifier: a novel and quantitative tool to study lipid accumulation in patient-derived circulating monocytes using confocal microscopy.J Lipid Res2017;58:2210-9 PMCID:PMC5665660

[39] Christensen JJ,Halvorsen B.Altered leukocyte distribution under hypercholesterolemia: A cross-sectional study in children with familial hypercholesterolemia.Atherosclerosis2017;256:67-74

[40] Combadière C,Rodero M.Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice.Circulation2008;117:1649-57

[41] Murphy AJ.Disordered haematopoiesis and athero-thrombosis.Eur Heart J2016;37:1113-21 PMCID:PMC4823636

[42] Fernandez-Ruiz I,Narasimhulu CA,Parthasarathy S.Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading.J Lipid Res2016;57:574-86 PMCID:PMC4808766

[43] Lian Z,Peng X.Monocyte phenotyping and management of lipoprotein X syndrome.J Clin Lipidol2020;14:850-8 PMCID:PMC7736232

[44] Bekkering S,Bernelot Moens S.Treatment with Statins does not revert trained immunity in patients with familial hypercholesterolemia.Cell Metab2019;30:1-2

[45] Li W,Siraj N.Autophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis.J Cell Mol Med2016;20:1664-72 PMCID:PMC4988293

[46] Tjaden K,Godfrey R,Pardali E.Low density lipoprotein interferes with intracellular signaling of monocytes resulting in impaired chemotaxis and enhanced chemokinesis.Int J Cardiol2018;255:160-5

[47] Bahrami A,Reiner Ž,Montecucco F.Inflammatory biomarkers for cardiovascular risk stratification in familial hypercholesterolemia.Rev Physiol Biochem Pharmacol2020;177:25-52

[48] Wang Y,Allahverdian S.Smooth muscle cells contribute the majority of foam cells in ApoE (Apolipoprotein E)-deficient mouse atherosclerosis.Arterioscler Thromb Vasc Biol2019;39:876-87 PMCID:PMC6482082

[49] Rendra E,Mossel DM,Harmsen MC.Reactive oxygen species (ROS) in macrophage activation and function in diabetes.Immunobiology2019;224:242-53

[50] Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing.Transl Res2019;204:39-50 PMCID:PMC6331222

[51] Kulcsar KA,Beck SE.Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection.JCI Insight2019;4:131774 PMCID:PMC6824443

[52] Codo AC,Monteiro LB.Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/Glycolysis-dependent axis.Cell Metab2020;32:498-9 PMCID:PMC7462530

[53] Ikeda Y,Bachuluun B,Ogawa Y.Aberrant activation of bone marrow Ly6C high monocytes in diabetic mice contributes to impaired glucose tolerance.PLoS One2020;15:e0229401 PMCID:PMC7041861

[54] Barrett TJ,Murphy AJ.Apolipoprotein AI promotes atherosclerosis regression in diabetic mice by suppressing myelopoiesis and plaque inflammation.Circulation2019;140:1170-84 PMCID:PMC6777860

[55] Csordas A.The biology behind the atherothrombotic effects of cigarette smoke.Nat Rev Cardiol2013;10:219-30

[56] Mehta S.Exposure of cigarette smoke condensate activates NLRP3 inflammasome in THP-1 cells in a stage-specific manner: An underlying role of innate immunity in atherosclerosis.Cell Signal2020;72:109645

[57] Kohashi K,Morisawa T.Effect of smoking status on monocyte tissue factor activity, carotid atherosclerosis and long-term prognosis in metabolic syndrome.Circ J2018;82:1418-27

[58] Cheng YC,Hu WL.Polyphenols and oxidative stress in atherosclerosis-related ischemic heart disease and stroke.Oxid Med Cell Longev2017;2017:8526438 PMCID:PMC5727797

[59] de Ronde MWJ,Moerland PD.High miR-124-3p expression identifies smoking individuals susceptible to atherosclerosis.Atherosclerosis2017;263:377-84

[60] Mehta S,Bhatia A.Exposure of cigarette smoke condensate activates NLRP3 inflammasome in vitro and in vivo: A connotation of innate immunity and atherosclerosis.Int Immunopharmacol2020;84:106561

[61] Studer RK,Craven PA.Protein kinase C signals thromboxane induced increases in fibronectin synthesis and TGF-beta bioactivity in mesangial cells.Kidney Int1995;48:422-30

[62] Mantovani A,Sozzani S,Vecchi A.The chemokine system in diverse forms of macrophage activation and polarization.Trends Immunol2004;25:677-86

[63] Boldrick JC,Diehn M.Stereotyped and specific gene expression programs in human innate immune responses to bacteria.Proc Natl Acad Sci U S A2002;99:972-7 PMCID:PMC117415

[64] Dalton DK,Keshav S,Bradley A.Multiple defects of immune cell function in mice with disrupted interferon-gamma genes.Science1993;259:1739-42

[65] Mosser DM.The many faces of macrophage activation.J Leukoc Biol2003;73:209-12

[66] Murray PJ.Protective and pathogenic functions of macrophage subsets.Nat Rev Immunol2011;11:723-37 PMCID:PMC3422549

[67] Wang N,Zen K.Molecular mechanisms that influence the macrophage m1-m2 polarization balance.Front Immunol2014;5:614 PMCID:PMC4246889

[68] Yang R,Wang L.Exosomes derived from M2b macrophages attenuate DSS-induced colitis.Front Immunol2019;10:2346 PMCID:PMC6843072

[69] Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. Macrophages in skin injury and repair.Immunobiology2011;216:753-62

[70] Jetten N,Gijbels MJ,De Winther MP.Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo.Angiogenesis2014;17:109-18

[71] Lee CG,Zhu Z.Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).J Exp Med2001;194:809-21 PMCID:PMC2195954

[72] Spencer M,Unal R.Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation.Am J Physiol Endocrinol Metab2010;299:E1016-27 PMCID:PMC3006260

[73] Mosser DM.Exploring the full spectrum of macrophage activation.Nat Rev Immunol2008;8:958-69 PMCID:PMC2724991

[74] Martinez FO,Mantovani A.Macrophage activation and polarization.Front Biosci2008;13:453-61

[75] Zizzo G,Monestier M.Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction.J Immunol2012;189:3508-20 PMCID:PMC3465703

[76] Zizzo G.IL-17 stimulates differentiation of human anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 and glucocorticoids.J Immunol2013;190:5237-46 PMCID:PMC3677729

[77] Ferrante CJ,Elson G.The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling.Inflammation2013;36:921-31 PMCID:PMC3710311

[78] Grinberg S,Wu D.Suppression of PLCbeta2 by endotoxin plays a role in the adenosine A(2A) receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype.Am J Pathol2009;175:2439-53 PMCID:PMC2789640

[79] Xu H,Chen W,Chen Z.Vascular macrophages in atherosclerosis.J Immunol Res2019;2019:4354786 PMCID:PMC6914912

[80] Pourcet B.Alternative macrophages in atherosclerosis: not always protective!.J Clin Invest2018;128:910-2 PMCID:PMC5824921

[81] Kadl A,Sharma PR.Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2.Circ Res2010;107:737-46 PMCID:PMC2941538

[82] Finn AV,Polavarapu R.Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques.J Am Coll Cardiol2012;59:166-77 PMCID:PMC3253238

[83] Boyle JJ,Kampfer T.Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection.Circ Res2012;110:20-33

[84] Nielsen MJ,Moestrup SK.Hemoglobin and heme scavenger receptors.Antioxid Redox Signal2010;12:261-73

[85] Philippidis P,Evans BJ.Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.Circ Res2004;94:119-26

[86] Landis RC,Domin J,Haskard DO.Haptoglobin genotype-dependent anti-inflammatory signaling in CD163(+) macrophages.Int J Inflam2013;2013:980327 PMCID:PMC3655560

[87] Boyle JJ.Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage.Curr Opin Lipidol2012;23:453-61

[88] Kockx MM,Knaapen MW.Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis.Arterioscler Thromb Vasc Biol2003;23:440-6

[89] Boyle JJ,Lo J.Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage.Arterioscler Thromb Vasc Biol2011;31:2685-91

[90] Gleissner CA,Little KM.CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages.J Immunol2010;184:4810-8 PMCID:PMC3418140

[91] Barlis P,Devries A.Optical coherence tomography assessment of vulnerable plaque rupture: predilection for the plaque 'shoulder'.Eur Heart J2008;29:2023

[92] Seneviratne A,Holvoet P.Biomechanical factors and macrophages in plaque stability.Cardiovasc Res2013;99:284-93

[93] Mantovani A,Locati M.Macrophage diversity and polarization in atherosclerosis: a question of balance.Arterioscler Thromb Vasc Biol2009;29:1419-23

[94] Chinetti-Gbaguidi G,Bouhlel MA.Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.Circ Res2011;108:985-95 PMCID:PMC3319502

[95] Tabas I.Macrophage death and defective inflammation resolution in atherosclerosis.Nat Rev Immunol2010;10:36-46 PMCID:PMC2854623

[96] Martinez FO,Gordon S.Alternative activation of macrophages: an immunologic functional perspective.Annu Rev Immunol2009;27:451-83

[97] Sindrilaru A,Wieschalka S.An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice.J Clin Invest2011;121:985-97 PMCID:PMC3049372

[98] Bories G,Vanhoutte J.Liver X receptor activation stimulates iron export in human alternative macrophages.Circ Res2013;113:1196-205 PMCID:PMC3989231

[99] Childs BG,Wijshake T,Campisi J.Senescent intimal foam cells are deleterious at all stages of atherosclerosis.Science2016;354:472-7 PMCID:PMC5112585

[100] Newby AC.Metalloproteinase production from macrophages - a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction.Exp Physiol2016;101:1327-37

[101] Shioi A.Plaque calcification during atherosclerosis progression and regression.J Atheroscler Thromb2018;25:294-303 PMCID:PMC5906181

[102] Reith S,Dettori R,Burgmaier M.Predictors for target lesion microcalcifications in patients with stable coronary artery disease: an optical coherence tomography study.Clin Res Cardiol2018;107:763-71

[103] Burgmaier M,Dettori R,Marx N.Co-localization of plaque macrophages with calcification is associated with a more vulnerable plaque phenotype and a greater calcification burden in coronary target segments as determined by OCT.PLoS One2018;13:e0205984 PMCID:PMC6200236

[104] Geeraerts X,Fendt SM.Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity.Front Immunol2017;8:289 PMCID:PMC5350105

[105] Mehla K.Metabolic regulation of macrophage polarization in cancer.Trends Cancer2019;5:822-34 PMCID:PMC7187927

[106] Qing J,Novák P,Yin K.Mitochondrial metabolism in regulating macrophage polarization: an emerging regulator of metabolic inflammatory diseases.Acta Biochim Biophys Sin (Shanghai)2020;52:917-26

[107] Verdeguer F.Macrophage heterogeneity and energy metabolism.Exp Cell Res2017;360:35-40

[108] Haschemi A,Gille L.The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism.Cell Metab2012;15:813-26 PMCID:PMC3370649

[109] Galván-Peña S.Metabolic reprograming in macrophage polarization.Front Immunol2014;5:420 PMCID:PMC4151090

[110] Zhang D,Huang H.Metabolic regulation of gene expression by histone lactylation.Nature2019;574:575-80 PMCID:PMC6818755

[111] Wang F,Vuckovic I.Glycolytic stimulation is not a requirement for M2 macrophage differentiation.Cell Metab2018;28:463-475.e4 PMCID:PMC5953001

[112] Palmieri EM,Baseler WA.Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase.Nat Commun2020;11:698 PMCID:PMC7000728

[113] Tannahill GM,Adamik J.Succinate is an inflammatory signal that induces IL-1β through HIF-1α.Nature2013;496:238-42 PMCID:PMC4031686

[114] Rath M,Kropf P,Munder M.Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages.Front Immunol2014;5:532 PMCID:PMC4209874

[115] Seim GL,John SV.Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation.Nat Metab2019;1:731-42 PMCID:PMC7108803

[116] Ménégaut L,Lagrost L.Fatty acid metabolism in macrophages: a target in cardio-metabolic diseases.Curr Opin Lipidol2017;28:19-26

[117] Rodriguez AE,Billingham LK.Serine Metabolism Supports Macrophage IL-1β Production.Cell Metab2019;29:1003-1011.e4 PMCID:PMC6447453

[118] Kieler M,Schabbauer G.More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization.FEBS J2021;288:3694-714

[119] Esteban-Martinez L.BNIP3L/NIX-dependent mitophagy regulates cell differentiation via metabolic reprogramming.Autophagy2018;14:915-17 PMCID:PMC6070009

[120] Wei Y,Gurung R.Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism.Circulation2018;138:2007-20

[121] den Bossche J, Baardman J, de Winther MP. Metabolic characterization of polarized M1 and M2 bone marrow-derived macrophages using real-time extracellular flux analysis.J Vis Exp2015; PMCID:PMC4692751

[122] Vats D,Odegaard JI.Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.Cell Metab2006;4:13-24 PMCID:PMC1904486

[123] Liu PS,Li X.α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming.Nat Immunol2017;18:985-94

[124] Simion V,Feinberg MW.LncRNAs in vascular biology and disease.Vascul Pharmacol2019;114:145-56 PMCID:PMC6078824

[125] Bonacina F,Catapano AL.Metabolic adaptations of cells at the vascular-immune interface during atherosclerosis.Mol Aspects Med2021;77:100918 PMCID:PMC7534736

[126] Hobson-Gutierrez SA.The metabolic axis of macrophage and immune cell polarization.Dis Model Mech2018;11:dmm034462 PMCID:PMC6124558

[127] Thapa B.Metabolic influence on macrophage polarization and pathogenesis.BMB Rep2019;52:360-72 PMCID:PMC6605523

[128] Biswas SK,Shalova IN.Macrophage polarization and plasticity in health and disease.Immunol Res2012;53:11-24

[129] Porcheray F,Rimaniol AC.Macrophage activation switching: an asset for the resolution of inflammation.Clin Exp Immunol2005;142:481-9 PMCID:PMC1809537

[130] Lee S,Nishio H.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol2011;22:317-26 PMCID:PMC3029904

[131] Abumaree MH,Kalionis B.Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages.Stem Cell Rev Rep2013;9:620-41

[132] Nahrendorf M.Abandoning M1/M2 for a network model of macrophage function.Circ Res2016;119:414-7 PMCID:PMC4965179

[133] Gordon S.Alternative activation of macrophages.Nat Rev Immunol2003;3:23-35

[134] Wolfs IM,de Winther MP.Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation.Thromb Haemost2011;106:763-71

[135] Sica A.Macrophage plasticity and polarization: in vivo veritas.J Clin Invest2012;122:787-95 PMCID:PMC3287223

[136] Verreck FA,Langenberg DM.Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.Proc Natl Acad Sci U S A2004;101:4560-5 PMCID:PMC384786

[137] Trus E,Gee K.Who's in charge here?.Cytokine2020;127:154939

[138] Stanley ER.CSF-1 receptor signaling in myeloid cells.Cold Spring Harb Perspect Biol2014;6:a021857-a021857 PMCID:PMC4031967

[139] Martinez FO.The M1 and M2 paradigm of macrophage activation: time for reassessment.F1000Prime Rep2014;6:13 PMCID:PMC3944738

[140] Brochériou I,Durand H.Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: implication in atherosclerosis.Atherosclerosis2011;214:316-24

[141] Waldo SW,Buono C.Heterogeneity of human macrophages in culture and in atherosclerotic plaques.Am J Pathol2008;172:1112-26 PMCID:PMC2276432

[142] Plenz G,Severs NJ.Smooth muscle cells express granulocyte-macrophage colony-stimulating factor in the undiseased and atherosclerotic human coronary artery.Arterioscler Thromb Vasc Biol1997;17:2489-99

[143] Kolodgie FD,Burke AP.Intraplaque hemorrhage and progression of coronary atheroma.N Engl J Med2003;349:2316-25

[144] Bae YS,Choi SH.Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2.Circ Res2009;104:210-8, 21p following 218 PMCID:PMC2720065

[145] Tits LJ, Stienstra R, van Lent PL, Netea MG, Joosten LA, Stalenhoef AF. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Krüppel-like factor 2.Atherosclerosis2011;214:345-9

[146] Hirose K,Shimada K.Different responses to oxidized low-density lipoproteins in human polarized macrophages.Lipids Health Dis2011;10:1 PMCID:PMC3022593

[147] Fan A,Wu H.Atheroprotective effect of oleoylethanolamide (OEA) targeting oxidized LDL.PLoS One2014;9:e85337 PMCID:PMC3896367

[148] Duewell P,Rayner KJ.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature2010;464:1357-61 PMCID:PMC2946640

[149] Fang L,Hartvigsen K.Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation.J Biol Chem2010;285:32343-51 PMCID:PMC2952235

[150] Sottero B,Longhi M.Expression and synthesis of TGFbeta1 is induced in macrophages by 9-oxononanoyl cholesterol, a major cholesteryl ester oxidation product.Biofactors2005;24:209-16

[151] Yang J,Tian L,Yang L.Sphingosine 1-phosphate (S1P)/S1P receptor2/3 axis promotes inflammatory M1 polarization of bone marrow-derived monocyte/macrophage via G(α)i/o/PI3K/JNK pathway.Cell Physiol Biochem2018;49:1677-93

[152] Hou L,Chang N.Macrophage sphingosine 1-phosphate receptor 2 blockade attenuates liver inflammation and fibrogenesis triggered by NLRP3 inflammasome.Front Immunol2020;11:1149 PMCID:PMC7333785

[153] Mitchell PL.Conjugated linoleic acid and atherosclerosis: studies in animal models.Biochem Cell Biol2008;86:293-301

[154] McCarthy C,Mooney D.IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.FASEB J2013;27:499-510

[155] Müller J,Heidecke CD.Differential S1P receptor profiles on M1- and M2-polarized macrophages affect macrophage cytokine production and Migration.Biomed Res Int2017;2017:7584621 PMCID:PMC5358463

[156] Park SJ,Kang S.Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4.Cell Signal2014;26:2249-58

[157] Kuang Y,Liu X.Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction.Cardiovasc Res2021;117:585-99

[158] Titos E,González-Périz A.Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype.J Immunol2011;187:5408-18

[159] Serhan CN,Martinod K.Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.J Exp Med2009;206:15-23 PMCID:PMC2626672

[160] Xiong W,Lu L.The macrophage C-type lectin receptor CLEC5A (MDL-1) expression is associated with early plaque progression and promotes macrophage survival.J Transl Med2017;15:234 PMCID:PMC5681784

[161] Chandra D,Alexander S.The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis.J Mol Cell Cardiol2019;126:50-9 PMCID:PMC7425077

[162] Di Gregoli K,Bianco R.Galectin-3 identifies a subset of macrophages with a potential beneficial role in atherosclerosis.Arterioscler Thromb Vasc Biol2020;40:1491-509 PMCID:PMC7253188

[163] Falcone C,Mazzucchelli I.Galectin-3 plasma levels and coronary artery disease: a new possible biomarker of acute coronary syndrome.Int J Immunopathol Pharmacol2011;24:905-13

[164] Varasteh Z,Mohanta S.Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (⁸⁹Zr)-DFO- Galectin3-F(ab')₂ mAb.Theranostics2021;11:1864-76 PMCID:PMC7778602

[165] Karlsson A,Matlak M.Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils.Glycobiology2009;19:16-20

[166] Erriah M,Fricker M.Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma.Respir Res2019;20:1 PMCID:PMC6318889

[167] Lepur A,Novak R,Nilsson UJ.Galectin-3 endocytosis by carbohydrate independent and dependent pathways in different macrophage like cell types.Biochim Biophys Acta2012;1820:804-18

[168] Henderson NC,Farnworth SL.Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis.Am J Pathol2008;172:288-98 PMCID:PMC2312353

[169] Cassaglia P,Betazza C.Genetic deletion of galectin-3 alters the temporal evolution of macrophage infiltration and healing affecting the cardiac remodeling and function after myocardial infarction in mice.Am J Pathol2020;190:1789-800

[170] MacKinnon AC,Hodkinson PS.Regulation of alternative macrophage activation by galectin-3.J Immunol2008;180:2650-8

[171] Shirakawa K,Kataoka M.IL (Interleukin)-10-STAT3-Galectin-3 axis is essential for osteopontin-producing reparative macrophage polarization after myocardial infarction.Circulation2018;138:2021-35

[172] Iacobini C,Ricci C.Accelerated lipid-induced atherogenesis in galectin-3-deficient mice: role of lipoxidation via receptor-mediated mechanisms.Arterioscler Thromb Vasc Biol2009;29:831-6

[173] Gleissner CA,Linden F.Galectin-3 binding protein, coronary artery disease and cardiovascular mortality: Insights from the LURIC study.Atherosclerosis2017;260:121-9

[174] Gao Z,Wang R,Li H.Galectin-3 is a potential mediator for atherosclerosis.J Immunol Res2020;2020:5284728 PMCID:PMC7042544

[175] Chinetti-Gbaguidi G,Staels B.Macrophage subsets in atherosclerosis.Nat Rev Cardiol2015;12:10-7

[176] Lee SG,Bong SK.Macrophage polarization and acceleration of atherosclerotic plaques in a swine model.PLoS One2018;13:e0193005 PMCID:PMC5862407

[177] Gong M,Ma A.STAT6 Upregulation promotes M2 macrophage polarization to suppress atherosclerosis.Med Sci Monit Basic Res2017;23:240-9 PMCID:PMC5484610

[178] Zhai C,Mujahid H.Selective inhibition of PI3K/Akt/mTOR signaling pathway regulates autophagy of macrophage and vulnerability of atherosclerotic plaque.PLoS One2014;9:e90563 PMCID:PMC3944201

[179] Yan H,Li Y.Insulin inhibits inflammation and promotes atherosclerotic plaque stability via PI3K-Akt pathway activation.Immunol Lett2016;170:7-14

[180] Vergadi E,Lyroni K,Tsatsanis C.Akt signaling pathway in macrophage activation and M1/M2 polarization.J Immunol2017;198:1006-14

[181] Linton MF,Babaev VR.Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis.Int J Mol Sci2019;20:2703 PMCID:PMC6600269

[182] Xu R,Wu Y.Role of KCa3.1 Channels in macrophage polarization and its relevance in atherosclerotic plaque instability.Arterioscler Thromb Vasc Biol2017;37:226-36

[183] Lawrence T.Transcriptional regulation of macrophage polarization: enabling diversity with identity.Nat Rev Immunol2011;11:750-61

[184] Biswas SK.Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat Immunol2010;11:889-96

[185] Bosisio D,Sironi M.Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide.Blood2002;99:3427-31

[186] Joffre J,Zeboudj L.Genetic and pharmacological inhibition of TREM-1 limits the development of experimental atherosclerosis.J Am Coll Cardiol2016;68:2776-93

[187] Yurtseven E,Baysal K.An update on the role of PCSK9 in atherosclerosis.J Atheroscler Thromb2020;27:909-18 PMCID:PMC7508721

[188] Tang ZH,Ren Z.New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway.Atherosclerosis2017;262:113-22

[189] Sokeechand BSH.Un-JAMming atherosclerotic arteries: JAM-L as a target to attenuate plaque development.Clin Sci (Lond)2019;133:1581-5

[190] Yang C,Chen W.Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques.J Exp Med2019;216:1182-98 PMCID:PMC6504213

[191] Hamers AA,Rassam F.Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis.Circ Res2012;110:428-38

[192] Hanna RN,Hubbeling HG.NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis.Circ Res2012;110:416-27 PMCID:PMC3309661

[193] Kahles F,Halim C.The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE^-/- mice by blocking monocyte/macrophage activation.Mol Metab2018;14:150-7

[194] Ji Y,Wang Z.PPARγ agonist rosiglitazone ameliorates LPS-induced inflammation in vascular smooth muscle cells via the TLR4/TRIF/IRF3/IP-10 signaling pathway.Cytokine2011;55:409-19

[195] Wen H,Liu Z.PEDF improves atherosclerotic plaque stability by inhibiting macrophage inflammation response.Int J Cardiol2017;235:37-41

[196] Yang SL,Wu JY,Tsao YP.Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma.Life Sci2010;87:26-35

[197] Takeda K,Shi W.Essential role of Stat6 in IL-4 signalling.Nature1996;380:627-30

[198] Liao X,Kapadia F.Krüppel-like factor 4 regulates macrophage polarization.J Clin Invest2011;121:2736-49 PMCID:PMC3223832

[199] Sharma N,Zhou G.Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report.Arterioscler Thromb Vasc Biol2012;32:2836-8

[200] Li B,Liu C.Kallistatin inhibits atherosclerotic inflammation by regulating macrophage polarization.Hum Gene Ther2019;30:339-51

[201] Fruman DA,Yballe CM.Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.Science1999;283:393-7

[202] Wu BW,Wu MS.Downregulation of microRNA-135b promotes atherosclerotic plaque stabilization in atherosclerotic mice by upregulating erythropoietin receptor.IUBMB Life2020;72:198-213

[203] Ricote M,Willson TM,Glass CK.The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.Nature1998;391:79-82

[204] Pascual G,Ogawa S.A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.Nature2005;437:759-63 PMCID:PMC1464798

[205] Gabunia K,Kelemen S.IL-19 halts progression of atherosclerotic plaque, polarizes, and increases cholesterol uptake and efflux in macrophages.Am J Pathol2016;186:1361-74 PMCID:PMC4861768

[206] Feig JE,Rong JX.Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques.Circulation2011;123:989-98 PMCID:PMC3131163

[207] Khallou-Laschet J,Fornasa G.Macrophage plasticity in experimental atherosclerosis.PLoS One2010;5:e8852 PMCID:PMC2810335

[208] Rocher C,Singal PK,Singla DK.Bone morphogenetic protein 7 polarizes THP-1 cells into M2 macrophages.Can J Physiol Pharmacol2012;90:947-51

[209] Boon MR,van der Pluijm G,Smit JW.Bone morphogenetic protein 7: a broad-spectrum growth factor with multiple target therapeutic potency.Cytokine Growth Factor Rev2011;22:221-9

[210] Singla DK,Wang J.BMP-7 treatment increases M2 macrophage differentiation and reduces inflammation and plaque formation in Apo E-/- mice.PLoS One2016;11:e0147897 PMCID:PMC4732822

[211] Rocher C.SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages.PLoS One2013;8:e84009 PMCID:PMC3869858

[212] Agil A,Ruiz R,Zen N.Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats.J Pineal Res2012;52:203-10

[213] Yang S,Chen S.MicroRNA-23a-5p promotes atherosclerotic plaque progression and vulnerability by repressing ATP-binding cassette transporter A1/G1 in macrophages.J Mol Cell Cardiol2018;123:139-49

[214] Leitinger N.Phenotypic polarization of macrophages in atherosclerosis.Arterioscler Thromb Vasc Biol2013;33:1120-6 PMCID:PMC3745999

[215] Bentzon JF,Virmani R.Mechanisms of plaque formation and rupture.Circ Res2014;114:1852-66

[216] Zhao Y,Ding S.Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy.J Pineal Res2017;62:e12378

[217] Zhou H,Zhu P,Reiter RJ.Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy.J Pineal Res2018;64:e12471

[218] He B,Xu L.The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury.J Pineal Res2016;60:313-26

[219] Zhai M,Zhang B.Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1β: In vivo and in vitro studies.J Pineal Res2017;63:e12433

[220] Xu L,Zhao Y.Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling.J Pineal Res2019;67:e12579

[221] Ma S,Feng J.Melatonin ameliorates the progression of atherosclerosis via mitophagy activation and NLRP3 inflammasome inhibition.Oxid Med Cell Longev2018;2018:9286458 PMCID:PMC6142770

[222] Ding S,Sheng X.Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner.J Pineal Res2019;67:e12581

[223] Qiao L,Liu M.Ginsenoside Rb1 enhances atherosclerotic plaque stability by improving autophagy and lipid metabolism in macrophage foam cells.Front Pharmacol2017;8:727 PMCID:PMC5660703

[224] Zhang X,Qiao L.Ginsenoside Rb1 enhances atherosclerotic plaque stability by skewing macrophages to the M2 phenotype.J Cell Mol Med2018;22:409-16 PMCID:PMC5742675

[225] Chen Z,Zhao Y.Oleoylethanolamide stabilizes atherosclerotic plaque through regulating macrophage polarization via AMPK-PPARα pathway.Biochem Biophys Res Commun2020;524:308-16

[226] Zhao Y,Peng L.Oleoylethanolamide alleviates macrophage formation via AMPK/PPARα/STAT3 pathway.Pharmacol Rep2018;70:1185-94

[227] Guo M,Sheng X.Ginsenoside Rg3 mitigates atherosclerosis progression in diabetic apoE-/- mice by skewing macrophages to the M2 phenotype.Front Pharmacol2018;9:464

[228] Chen F,Cao G,Yuan Z.Molecular analysis of curcumin-induced polarization of murine RAW264.7 macrophages.J Cardiovasc Pharmacol2014;63:544-52

[229] Jacob A,Zhou M.Mechanism of the anti-inflammatory effect of curcumin: PPAR-gamma activation.PPAR Res2007;2007:89369 PMCID:PMC2234255

[230] Meng Z,Deng Q,Niu XL.Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways.Acta Pharmacol Sin2013;34:901-11 PMCID:PMC4002611

[231] Zhou Y,Wang X.Curcumin modulates macrophage polarization through the inhibition of the toll-like receptor 4 expression and its signaling pathways.Cell Physiol Biochem2015;36:631-41

[232] Cao J,Tian L.Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages.J Transl Med2014;12:266 PMCID:PMC4205290

[233] Aharoni S,Aviram M.Pomegranate juice polyphenols induce a phenotypic switch in macrophage polarization favoring a M2 anti-inflammatory state.Biofactors2015;41:44-51

[234] Wang N,Ma Z.Combination of tanshinone IIA and astragaloside IV attenuate atherosclerotic plaque vulnerability in ApoE(-/-) mice by activating PI3K/AKT signaling and suppressing TRL4/NF-κB signaling.Biomed Pharmacother2020;123:109729

[235] Hara T,Tanaka K.Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice.Atherosclerosis2015;242:639-46

[236] Skiba DS,Mikolajczyk TP.Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis.Br J Pharmacol2017;174:4055-69 PMCID:PMC5659999

[237] Derosa G,Fogari E.Sitagliptin added to previously taken antidiabetic agents on insulin resistance and lipid profile: a 2-year study evaluation.Fundam Clin Pharmacol2014;28:221-9

[238] Brenner C,Kühlenthal S.DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages.Int J Cardiol2015;199:163-9

[239] Shen L,Nie P.Sulindac-derived retinoid X receptor-α modulator attenuates atherosclerotic plaque progression and destabilization in ApoE^-/- mice.Br J Pharmacol2019;176:2559-72

[240] Singla DK,Tavakoli Dargani Z.Exosome treatment enhances anti-inflammatory M2 Macrophages and reduces inflammation-induced pyroptosis in doxorubicin-induced cardiomyopathy.Cells2019;8:1224 PMCID:PMC6830113