Monocyte-Macrophages and T Cells in Atherosclerosis
Authors: Ira Tabas, Andrew H. Lichtman
Journal: Immunity (2017)

Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in affecting these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies. Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein-B-containing lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving and can lead to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis to monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance between regulatory and effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in affecting these responses. Herein, we review select topics that shed light on these processes and suggest new treatment strategies. Atherogenesis is initiated by the entry and retention of apolipoprotein-B-containing lipoproteins (apoB LPs) into the subendothelial space, or "intima," at regions of disturbed blood flow in medium-sized arteries (Williams and Tabas, 1995Williams K.J. Tabas I. The response-to-retention hypothesis of early atherogenesis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar, Fogelstrand and Borén, 2012Fogelstrand P. Borén J. Retention of atherogenic lipoproteins in the artery wall and its role in atherogenesis.Nutr. Metab. Cardiovasc. Dis. 2012; 22: 1-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The amount of apoB LP retention is determined by the concentration of apoB LPs in the blood, the age and metabolic state of the individual, and genetic and environmental factors. These considerations affect arterial wall biology, including variations in subendothelial proteoglycans that retain apoB LPs and factors that alter endothelial permeability. Initially, some of the lipoprotein lipid is internalized by resident CD11c+ myeloid cells, and experimental depletion of these cells suppresses the early accumulation of foam cells and intracellular lipids (Paulson et al., 2010Paulson K.E. Zhu S.N. Chen M. Nurmohamed S. Jongstra-Bilen J. Cybulsky M.I. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis.Circ. Res. 2010; 106: 383-390Crossref PubMed Scopus (169) Google Scholar). Then, certain lipid and protein components of subendothelial apoB LPs, particularly after oxidative modification, take on properties of damage-associated molecular patterns (DAMPs) and thereby trigger an inflammatory response (Glass and Witztum, 2001Glass C.K. Witztum J.L. Atherosclerosis. the road ahead.Cell. 2001; 104: 503-516Abstract Full Text Full Text PDF PubMed Scopus (2166) Google Scholar, Lusis, 2000Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Crossref PubMed Scopus (3547) Google Scholar). This response activates endothelial cells and, together with flow-mediated changes in these cells (Jongstra-Bilen et al., 2006Jongstra-Bilen J. Haidari M. Zhu S.N. Chen M. Guha D. Cybulsky M.I. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis.J. Exp. Med. 2006; 203: 2073-2083Crossref PubMed Scopus (206) Google Scholar, Gimbrone and García-Cardeña, 2013Gimbrone Jr., M.A. García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis.Cardiovasc. Pathol. 2013; 22: 9-15Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, promotes the entry into the intima of bone-marrow-derived monocytes (Tacke et al., 2007Tacke F. Alvarez D. Kaplan T.J. Jakubzick C. Spanbroek R. Llodra J. Garin A. Liu J. Mack M. van Rooijen N. et al.Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.J. Clin. Invest. 2007; 117: 185-194Crossref PubMed Scopus (741) Google Scholar, Swirski et al., 2016Swirski F.K. Robbins C.S. Nahrendorf M. Development and function of arterial and cardiac macrophages.Trends Immunol. 2016; 37: 32-40Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The Ly6Chi subpopulation of monocytes in the intima differentiates into macrophages, which, in progressing lesions, take on an inflammatory phenotype (Tacke et al., 2007Tacke F. Alvarez D. Kaplan T.J. Jakubzick C. Spanbroek R. Llodra J. Garin A. Liu J. Mack M. van Rooijen N. et al.Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.J. Clin. Invest. 2007; 117: 185-194Crossref PubMed Scopus (741) Google Scholar, Swirski et al., 2007Swirski F.K. Libby P. Aikawa E. Alcaide P. Luscinskas F.W. Weissleder R. Pittet M.J. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.J. Clin. Invest. 2007; 117: 195-205Crossref PubMed Scopus (698) Google Scholar). In part as a result of the accumulation of inflammatory macrophages and dendritic cell (DC) activation, an inflammatory adaptive immune response involving primarily T helper 1 (Th1) cells, but also Th17 and Th2 cells and B cells, develops in conjunction with a progressive decrease in regulatory T (Treg) cells (Witztum and Lichtman, 2014Witztum J.L. Lichtman A.H. The influence of innate and adaptive immune responses on atherosclerosis.Annu. Rev. Pathol. 2014; 9: 73-102Crossref PubMed Scopus (89) Google Scholar). Other immune cells, including neutrophils and platelet-neutrophil aggregates, innate immune cells, natural killer cells, mast cells, and eosinophils, are present in human atheroma and have been shown to promote atherosclerosis via additional mechanisms in mouse models (Witztum and Lichtman, 2014Witztum J.L. Lichtman A.H. The influence of innate and adaptive immune responses on atherosclerosis.Annu. Rev. Pathol. 2014; 9: 73-102Crossref PubMed Scopus (89) Google Scholar). Accompanying this immune cell reaction is the accumulation of myofibroblasts in the intima; these arise from medial smooth muscle cells and other sources and are referred to as vascular smooth muscle cells (VSMCs) (Bennett et al., 2016Bennett M.R. Sinha S. Owens G.K. Vascular Smooth Muscle Cells in Atherosclerosis.Circ. Res. 2016; 118: 692-702Crossref PubMed Scopus (139) Google Scholar). These cells are rich sources of extracellular matrix, which most likely represents a "scar" response to inflammation and the ongoing vascular injury. In a physiologic post-inflammatory response, macrophages and other inflammatory cells secrete molecules and carry out functions that dampen the inflammatory response and promote tissue repair (Serhan et al., 2007Serhan C.N. Brain S.D. Buckley C.D. Gilroy D.W. Haslett C. O'Neill L.A. Perretti M. Rossi A.G. Wallace J.L. Resolution of inflammation: state of the art, definitions and terms.FASEB J. 2007; 21: 325-332Crossref PubMed Scopus (592) Google Scholar, Nathan and Ding, 2010Nathan C. Ding A. Nonresolving inflammation.Cell. 2010; 140: 871-882Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar). However, as will be explained later in this review, this so-called resolution response can go awry in the setting of atherosclerosis. Impaired resolution in atherosclerotic lesions leads to sustained, non-resolving, and maladaptive inflammation that promotes plaque progression and, in humans, triggers acute thrombo-occlusive cardiovascular events (Merched et al., 2008Merched 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. 2008; 22: 3595-3606Crossref PubMed Scopus (234) Google Scholar, Tabas, 2010Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis.Nat. Rev. Immunol. 2010; 10: 36-46Crossref PubMed Scopus (514) Google Scholar, Viola and Soehnlein, 2015Viola J. Soehnlein O. Atherosclerosis - A matter of unresolved inflammation.Semin. Immunol. 2015; 27: 184-193Crossref PubMed Scopus (0) Google Scholar). The pathological features of clinically dangerous plaques include large areas of necrosis and thinning of an overlying collagenous, or fibrous, cap. When a breach forms in the fibrous cap, blood is exposed to thrombogenic material in the lesion, and acute occlusive thrombosis with tissue infarction can ensue (Virmani et al., 2002Virmani R. Burke A.P. Kolodgie F.D. Farb A. Vulnerable plaque: the pathology of unstable coronary lesions.J. Interv. Cardiol. 2002; 15: 439-446Crossref PubMed Google Scholar, Libby, 2013Libby P. Mechanisms of acute coronary syndromes and their implications for therapy.N. Engl. J. Med. 2013; 368: 2004-2013Crossref PubMed Scopus (354) Google Scholar). However, acute thrombotic vascular events can also occur in the vicinity of more fibrous, non-necrotic plaques that are characterized by endothelial erosion (Libby, 2017Libby P. Superficial erosion and the precision management of acute coronary syndromes: not one-size-fits-all.Eur. Heart J. 2017; 38: 801-803PubMed Google Scholar). Studies in mice have suggested that this latter process is promoted by flow disturbance and neutrophil-mediated effects on endothelial cells (Franck et al., 2017Franck G. Mawson T. Sausen G. Salinas M. Masson G.S. Cole A. Beltrami-Moreira M. Chatzizisis Y. Quillard T. Tesmenitsky Y. et al.Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.Circ. Res. 2017; 121: 31-42Crossref PubMed Scopus (2) Google Scholar). In the sections that follow, we will review a selective subset of innate and adaptive immune processes that have recently come to light as affecting atherogenesis and/or plaque progression. The reader is referred to the reviews cited above and original references cited in these reviews for the many important immune processes in atherosclerosis that are not included herein. The abundance of monocytes in the circulation, particularly those of the CD14++ subpopulation in humans and the Ly6Chi subpopulation in mice, is strongly correlated with atherosclerotic vascular disease in humans and the development of atherosclerotic lesions in mice (Olivares et al., 1993Olivares R. Ducimetière P. Claude J.R. Monocyte count: a risk factor for coronary heart disease?.Am. J. Epidemiol. 1993; 137: 49-53Crossref PubMed Google Scholar, Murphy and Tall, 2016Murphy A.J. Tall A.R. Disordered haematopoiesis and athero-thrombosis.Eur. Heart J. 2016; 37: 1113-1121Crossref PubMed Scopus (16) Google Scholar). In this context, recent studies have provided fascinating new insight into the regulatory mechanisms of monocytosis relevant to atherosclerosis (Figure 1). The role of the sympathetic nervous system (SNS) came to light as researchers sought to explain why atherosclerosis accelerates after myocardial infarction (MI). In the setting of an inflammatory response, Ly6Chi monocytes initially give rise to macrophages on the inflammatory end of the inflammatory-resolution spectrum, and as will be discussed in the following paragraphs, these macrophages promote atherosclerosis progression (Swirski et al., 2007Swirski F.K. Libby P. Aikawa E. Alcaide P. Luscinskas F.W. Weissleder R. Pittet M.J. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.J. Clin. Invest. 2007; 117: 195-205Crossref PubMed Scopus (698) Google Scholar). A substantial portion of Ly6Chi monocytes that contribute to atherosclerosis originate from the spleen, which becomes populated with bone-marrow-derived hematopoietic stem and progenitor cells (HSPCs) and carries out extramedullary hematopoiesis (Robbins et al., 2012Robbins C.S. Chudnovskiy A. Rauch P.J. Figueiredo J.L. Iwamoto Y. Gorbatov R. Etzrodt M. Weber G.F. Ueno T. van Rooijen N. et al.Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions.Circulation. 2012; 125: 364-374Crossref PubMed Scopus (187) Google Scholar). In this context, mouse studies suggest that a key mechanism of post-MI atherosclerosis is SNS-mediated release of HSPCs from the bone marrow, which leads to seeding of the spleen, elevated extramedullary hematopoiesis, and increased release of Ly6Chi monocytes, which drive atherogenesis (Dutta et al., 2012Dutta P. Courties G. Wei Y. Leuschner F. Gorbatov R. Robbins C.S. Iwamoto Y. Thompson B. Carlson A.L. Heidt T. et al.Myocardial infarction accelerates atherosclerosis.Nature. 2012; 487: 325-329Crossref PubMed Scopus (388) Google Scholar). Further evidence suggests that other stress-related events that are known to be risk factors for atherosclerotic disease, such as psychosocial stress, might work through a similar mechanism (Heidt et al., 2014Heidt T. Sager H.B. Courties G. Dutta P. Iwamoto Y. Zaltsman A. von Zur Muhlen C. Bode C. Fricchione G.L. Denninger J. et al.Chronic variable stress activates hematopoietic stem cells.Nat. Med. 2014; 20: 754-758Crossref PubMed Scopus (161) Google Scholar). How these concepts apply to human atherothrombotic vascular disease remains an important area for future study, particularly in view of uncertainties related to the functions of CD14++ monocytes in humans (Hilgendorf and Swirski, 2012Hilgendorf I. Swirski F.K. Making a difference: monocyte heterogeneity in cardiovascular disease.Curr. Atheroscler. Rep. 2012; 14: 450-459Crossref PubMed Scopus (0) Google Scholar). Hypercholesterolemia also promotes monocytosis, particularly Ly6Chi monocytosis, in mice (Swirski et al., 2007Swirski F.K. Libby P. Aikawa E. Alcaide P. Luscinskas F.W. Weissleder R. Pittet M.J. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.J. Clin. Invest. 2007; 117: 195-205Crossref PubMed Scopus (698) Google Scholar), and defective cholesterol efflux in HSPCs effected by genetic targeting of cholesterol efflux proteins can also exacerbate Ly6Chi monocytosis (Murphy and Tall, 2016Murphy A.J. Tall A.R. Disordered haematopoiesis and athero-thrombosis.Eur. Heart J. 2016; 37: 1113-1121Crossref PubMed Scopus (16) Google Scholar) (Figure 2). The mechanism responsible for cholesterol-induced monocytosis involves expansion of Lin−cKit+Sca1+ HSPCs in the marrow compartment (Murphy and Tall, 2016Murphy A.J. Tall A.R. Disordered haematopoiesis and athero-thrombosis.Eur. Heart J. 2016; 37: 1113-1121Crossref PubMed Scopus (16) Google Scholar). Mechanistic studies revealed that cholesterol-mediated changes in the plasma membrane of HSPCs lead to elevated cell-surface expression of the common β-subunit of the interleukin-3 (IL-3) and granulocyte-monocyte colony-stimulating factor (GM-CSF) receptors and increased sensing of two key HSPC growth factors, IL-3 and GM-CSF (Yvan-Charvet et al., 2010Yvan-Charvet L. Pagler T. Gautier E.L. Avagyan S. Siry R.L. Han S. Welch C.L. Wang N. Randolph G.J. Snoeck H.W. Tall A.R. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.Science. 2010; 328: 1689-1693Crossref PubMed Scopus (289) Google Scholar). There is also evidence that hypercholesterolemia, presumably by increasing the cellular content of cholesterol, decreases the expression of Rb, a tumor suppressor that limits HSPC proliferation, and increases the expression of cyclins B1, D1, and E1 in HSPCs (Seijkens et al., 2014Seijkens T. Hoeksema M.A. Beckers L. Smeets E. Meiler S. Levels J. Tjwa M. de Winther M.P. Lutgens E. Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis.FASEB J. 2014; 28: 2202-2213Crossref PubMed Scopus (31) Google Scholar). Interestingly, when normocholesterolemic recipient mice were transplanted with bone marrow from either normocholesterolemic or hypercholesterolemic donor mice, the HSPCs of hypercholesterolemic donor origin showed increased proliferation 10 weeks later (Seijkens et al., 2014Seijkens T. Hoeksema M.A. Beckers L. Smeets E. Meiler S. Levels J. Tjwa M. de Winther M.P. Lutgens E. Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis.FASEB J. 2014; 28: 2202-2213Crossref PubMed Scopus (31) Google Scholar). These data suggest a long-lived, cell-intrinsic effect of hypercholesterolemia on HSPCs, perhaps as a result of epigenetic changes in the donor HSPCs. Moreover, when Ldlr−/− mice were transplanted with bone marrow cells from hypercholesterolemic or normocholesterolemic mice and then fed a Western-type diet rich in cholesterol and saturated fats, the mice that had received that hypercholesterolemic bone marrow developed larger and more advanced lesions. This increase in atherosclerosis was accompanied by a higher number of lesional leukocytes derived from the hypercholesterolemic mouse bone marrow cells and overall increases in plaque macrophages, granulocytes, and T cells. Other recent studies have taken advantage of the fact that leukocytosis in myeloproliferative disease (MPD) is associated with atherothrombotic vascular disease (Murphy and Tall, 2016Murphy A.J. Tall A.R. Disordered haematopoiesis and athero-thrombosis.Eur. Heart J. 2016; 37: 1113-1121Crossref PubMed Scopus (16) Google Scholar). For example, a loss-of-function polymorphism in the gene encoding a signaling adaptor protein called LNK (SH2B3) is associated with both MPD and atherosclerosis (McMullin et al., 2011McMullin M.F. Wu C. Percy M.J. Tong W. A nonsynonymous LNK polymorphism associated with idiopathic erythrocytosis.Am. J. Hematol. 2011; 86: 962-964Crossref PubMed Scopus (0) Google Scholar, Deloukas et al., 2013Deloukas P. Kanoni S. Willenborg C. Farrall M. Assimes T.L. Thompson J.R. Ingelsson E. Saleheen D. Erdmann J. Goldstein B.A. et al.CARDIoGRAMplusC4D ConsortiumDIAGRAM ConsortiumCARDIOGENICS ConsortiumMuTHER ConsortiumWellcome Trust Case Control ConsortiumLarge-scale association analysis identifies new risk loci for coronary artery disease.Nat. Genet. 2013; 45: 25-33Crossref PubMed Scopus (712) Google Scholar). Moreover, somatic gain-of-function mutations in JAK2 kinase are also associated with MPD and atherosclerotic disease (Viny and Levine, 2014Viny A.D. Levine R.L. Genetics of myeloproliferative neoplasms.Cancer J. 2014; 20: 61-65Crossref PubMed Scopus (0) Google Scholar). Although processes related to neutrophils and platelets most likely contribute to the mechanism of this association, there is also a link to monocytosis. In this context, genetic targeting of Lnk in Lnk−/−Ldlr−/− mice fed a Western diet has been found to cause hypercholesterolemia-dependent monocytosis, which is associated with increased amounts of the pro-atherogenic chemokine monocyte chemotactic protein-1 (MCP-1; also known as CCL2) (Wang et al., 2016Wang W. Tang Y. Wang Y. Tascau L. Balcerek J. Tong W. Levine R.L. Welch C. Tall A.R. Wang N. LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis.Circ. Res. 2016; 119: e91-e103Crossref PubMed Scopus (0) Google Scholar). Most importantly, these mice demonstrate increases in atherosclerotic lesion area, lesional macrophages, Ly6Chi monocyte entry into lesions, and atherogenic platelet-monocyte aggregates (Wang et al., 2016Wang W. Tang Y. Wang Y. Tascau L. Balcerek J. Tong W. Levine R.L. Welch C. Tall A.R. Wang N. LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis.Circ. Res. 2016; 119: e91-e103Crossref PubMed Scopus (0) Google Scholar). Synergy between hypercholesterolemia and LNK deficiency leads to further increases in IL-3-GM-CSF receptor signaling in bone marrow HSPCs. Further insight into some of these processes emerges from a study showing that Glut1-mediated glucose uptake by inflammatory myeloid cells promotes myeloproliferation in mice with either defective cholesterol efflux or myeloproliferative disorders (Gautier et al., 2013Gautier E.L. Westerterp M. Bhagwat N. Cremers S. Shih A. Abdel-Wahab O. Lütjohann D. Randolph G.J. Levine R.L. Tall A.R. Yvan-Charvet L. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders.J. Exp. Med. 2013; 210: 339-353Crossref PubMed Scopus (29) Google Scholar). In view of the link between glycolysis and inflammatory myeloid cell function (Van den Bossche et al., 2017Van den Bossche J. O'Neill L.A. Menon D. Macrophage immunometabolism: Where are we (going)?.Trends Immunol. 2017; 38: 395-406Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), the authors propose that Glut1-mediated glucose uptake provides the energy necessary for inflammatory myeloid cell proliferation. Ly6Clo monocytes derive from Ly6Chi monocytes and serve an endothelial maintenance "patrolling" function in the circulation, but their roles in tissues have become increasingly unclear, and it is not even certain whether they differentiate into macrophages (Jakubzick et al., 2017Jakubzick C.V. Randolph G.J. Henson P.M. Monocyte differentiation and antigen-presenting functions.Nat. Rev. Immunol. 2017; 17: 349-362Crossref PubMed Scopus (31) Google Scholar). As such, the role of Ly6Clo monocytes in atherosclerosis is poorly understood. In one study, investigators tested the effect of targeting the nuclear receptor Nr4a1 (Nur77), which is required for the differentiation and survival of Ly6Clo monocytes (Hanna et al., 2011Hanna R.N. Carlin L.M. Hubbeling H.G. Nackiewicz D. Green A.M. Punt J.A. Geissmann F. Hedrick C.C. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes.Nat. Immunol. 2011; 12: 778-785Crossref PubMed Scopus (221) Google Scholar). Two models of mouse atherosclerosis with genetic targeting of Nr4a1—Western-diet-fed Ldlr−/− mice lacking hematopoietic Nr4a1 and Apoe−/− mice with germline targeting of Nr4a1—demonstrated increased atherosclerosis, and this was associated with an increase in the proportion of lesional macrophages that had an inflammatory or a resolving phenotype (Hanna et al., 2011Hanna R.N. Carlin L.M. Hubbeling H.G. Nackiewicz D. Green A.M. Punt J.A. Geissmann F. Hedrick C.C. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes.Nat. Immunol. 2011; 12: 778-785Crossref PubMed Scopus (221) Google Scholar). Although one interpretation of this finding is that Ly6Clo monocytes directly give rise to resolving macrophages that regulate the inflammatory response, another possible interpretation is that Nr4a1 is required for the conversion of Ly6Chi monocytes into resolving macrophages (Hilgendorf et al., 2014Hilgendorf I. Gerhardt L.M. Tan T.C. Winter C. Holderried T.A. Chousterman B.G. Iwamoto Y. Liao R. Zirlik A. Scherer-Crosbie M. et al.Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium.Circ. Res. 2014; 114: 1611-1622Crossref PubMed Scopus (142) Google Scholar). For example, Ly6Chi monocytes infiltrate the heart immediately after MI and then, during the repair phase, give rise to Ly6Clo macrophages with resolving properties. However, in mice lacking hematopoietic Nr4a1, infiltrating Ly6Chi monocytes differentiate into highly inflammatory macrophages that are unable to carry out tissue repair. If applicable to atherosclerosis, the data from the Nr4a1-deficient mouse study above could suggest that Ly6hi monocytes give rise to reparative macrophages in atherosclerotic lesions in an Nr4a1-dependent manner. Consistent with this idea, a recent study showed that Ly6Chi monocytes are the source of resolving macrophages during atherosclerotic plaque regression (Rahman et al., 2017Rahman K. Vengrenyuk Y. Ramsey S.A. Vila N.R. Girgis N.M. Liu J. Gusarova V. Gromada J. Weinstock A. Moore K.J. et al.Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression.J. Clin. Invest. 2017; 127: 2904-2915Crossref PubMed Scopus (0) Google Scholar). Macrophage functions can vary widely depending on a number of interacting variables and factors, including local environment ("tissue niche") (Gosselin et al., 2014Gosselin D. Link V.M. Romanoski C.E. Fonseca G.J. Eichenfield D.Z. Spann N.J. Stender J.D. Chun H.B. Garner H. Geissmann F. Glass C.K. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities.Cell. 2014; 159: 1327-1340Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, Lavin et al., 2014Lavin Y. 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Identification of CAD candidate genes in GWAS loci and their expression in vascular cells.J. Lipid Res. 2013; 54: 1894-1905Crossref PubMed Scopus (42) Google Scholar, Chen et al., 2015Chen H.H. Keyhanian K. Zhou X. Vilmundarson R.O. Almontashiri N.A. Cruz S.A. Pandey N.R. Lerma Yap N. Ho T. Stewart C.A. et al.IRF2BP2 reduces macrophage inflammation and susceptibility to atherosclerosis.Circ. Res. 2015; 117: 671-683Crossref PubMed Scopus (8) Google Scholar, Wu et al., 2016Wu X.Q. Dai Y. Yang Y. Huang C. Meng X.M. Wu B.M. Li J. Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation.Immunology. 2016; 148: 237-248Crossref PubMed Scopus (23) Google Scholar, Amit et al., 2016Amit I. Winter D.R. Jung S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis.Nat. Immunol. 2016; 17: 18-25Crossref PubMed Scopus (71) Google Scholar, Phan et al., 2017Phan A.T. 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By secreting cytokines, proteases, and other factors, inflammatory macrophages increase the cellular expansion of lesions and cause plaque morphological changes that can trigger plaque rupture and acute lumenal thrombosis. Two key changes promoted by inflammatory macrophages are plaque necrosis and thinning of a protective collagenous scar (fibrous cap). Conversely, resolving macrophages carry out functions that are associated with plaque stabilization. These functions include clearing dead cells (efferocytosis), which stabilize plaques by preventing post-apoptotic cellular necrosis; secreting collagen that can form a protective scar over the lesion; and producing proteins and lipids that quell inflammation and promote tissue repair. Molecular profiling of lesional macrophages at various stages of lesion progression and regression has demonstrated heterogeneity suggestive of these different functions (Peled and Fisher, 2014Peled M. Fisher E.A. Dynamic aspects of macrophage polarization during atherosclerosis progression and regression.Front. Immunol. 2014; 5: 579Crossref PubMed Scopus (50) Google Scholar). One such study using immunohistochemistry and RNA profiling showed that CD68+ macrophages at both ends of the inflammation-resolution spectrum accumulate as atherosclerotic lesions develop (Stöger et al., 2012Stöger J.L. Gijbels M.J. van der Velden S. Manca M. van der Loos C.M. Biessen E.A. Daemen M.J. Lutgens E. de Winther M.P. Distribution of macrophage polarization markers in human ather