Tabas-2017-Monocyte-Macrophages and T Cells in.pdf

ImmunityReviewMonocyte-MacrophagesandTCellsinAtherosclerosisIra Tabas1,*and Andrew H.Lichtman2,*1Departments of Medicine,Physiology,and Pathology&Cell Biology,Columbia University Medical Center,New York,NY 10032,USA2Department of Pathology,Brigham and Womens Hospital and Harvard Medical School,Boston,MA 02115,USA*Correspondence:iat1columbia.edu(I.T.),alichtmanbwh.harvard.edu(A.H.L.)https:/doi.org/10.1016/j.immuni.2017.09.008Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulationof apolipoprotein-B-containing lipoproteins,immune and vascular wall cells,and extracellular matrix.Thelipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immuneresponse,dominated by monocyte-macrophages,and then an adaptive immune response.These inflamma-tory 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 hematopoiesisto monocyte changes and macrophage activation.The adaptive immune response is regulated primarily bymechanisms that affect the balance between regulatory and effector T cells.Mechanisms related to cellularcholesterol,phenotypic plasticity,metabolism,andaging play key roles in affecting these responses.Herein,we review select topics that shed light on these processes and suggest new treatment strategies.A Brief Overview of Atherogenesis and AtheroscleroticPlaque ProgressionAtherogenesis is initiated by the entry and retention of apolipo-protein-B-containing lipoproteins(apoB LPs)into the subendo-thelial space,or intima,at regions of disturbed blood flow inmedium-sized arteries(Williams and Tabas,1995;Fogelstrandand Bore n,2012).The amount of apoB LP retention is deter-mined by the concentration of apoB LPs in the blood,the ageand metabolic state of the individual,and genetic and environ-mental factors.These considerations affect arterial wall biology,including variations in subendothelial proteoglycans that retainapoB 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 sup-presses the early accumulation of foam cells and intracellularlipids(Paulson et al.,2010).Then,certain lipid and protein com-ponents of subendothelial apoB LPs,particularly after oxidativemodification,take on properties of damage-associated molecu-lar patterns(DAMPs)and thereby trigger an inflammatoryresponse(Glass and Witztum,2001;Lusis,2000).This responseactivates endothelial cells and,together with flow-mediatedchanges in these cells(Jongstra-Bilen et al.,2006;Gimbroneand Garc a-Carden a,2013),promotes the entry into the intimaof bone-marrow-derived monocytes(Tacke et al.,2007;Swirskiet al.,2016).The Ly6Chisubpopulation of monocytes in the in-tima differentiates into macrophages,which,in progressing le-sions,take on an inflammatory phenotype(Tacke et al.,2007;Swirski et al.,2007).In part as a result of the accumulation of in-flammatory macrophages and dendritic cell(DC)activation,aninflammatory adaptive immune response involving primarilyThelper 1(Th1)cells,butalsoTh17 andTh2cellsandBcells,de-velops in conjunction with a progressive decrease in regulatoryT(Treg)cells(Witztum and Lichtman,2014).Other immune cells,including neutrophils and platelet-neutrophil aggregates,innateimmune cells,natural killer cells,mast cells,and eosinophils,are present in human atheroma and have been shown to pro-mote atherosclerosis via additional mechanisms in mousemodels(Witztum and Lichtman,2014).Accompanying thisimmune cell reaction is the accumulation of myofibroblasts inthe intima;these arise from medial smooth muscle cells andother sources and are referred to as vascular smooth musclecells(VSMCs)(Bennett et al.,2016).These cells are rich sourcesof extracellular matrix,which most likely represents a scarresponse to inflammation and the ongoing vascular injury.In a physiologic post-inflammatory response,macrophagesand other inflammatory cells secrete molecules and carry outfunctions that dampen the inflammatory response and promotetissue repair(Serhan et al.,2007;Nathan and Ding,2010).How-ever,aswillbeexplainedlaterinthisreview,thisso-calledresolu-tion response can go awry in the setting of atherosclerosis.Impaired resolution in atherosclerotic lesions leads to sustained,non-resolving,and maladaptive inflammation that promotes pla-que progression and,in humans,triggers acute thrombo-occlu-sive cardiovascular events(Merched et al.,2008;Tabas,2010;Viola and Soehnlein,2015).The pathological features of clinicallydangerousplaquesincludelargeareasofnecrosisandthinningofanoverlyingcollagenous,orfibrous,cap.Whenabreachformsinthefibrouscap,blood isexposed tothrombogenic materialin thelesion,and acute occlusive thrombosis with tissue infarction canensue(Virmani et al.,2002;Libby,2013).However,acute throm-boticvasculareventscanalsooccurinthevicinityofmorefibrous,non-necrotic plaques that are characterized by endothelialerosion(Libby,2017).Studies in mice have suggested that thislatter process is promoted by flow disturbance and neutrophil-mediated effects on endothelial cells(Franck et al.,2017).In the sections that follow,we will review a selective subset ofinnate and adaptive immune processes that have recently cometo light as affecting atherogenesis and/or plaque progression.The reader is referred to the reviews cited above and original ref-erences cited in these reviews for the many important immuneprocesses in atherosclerosis that are not included herein.Changes in Monocyte Dynamics Contribute toAtherogenesisThe abundance of monocytes in the circulation,particularlythose of the CD14+subpopulation in humans and the Ly6ChiImmunity 47,October 17,2017 2017 Elsevier Inc.621subpopulation in mice,is strongly correlated with atheroscle-rotic vascular disease in humans and the development ofatherosclerotic lesions in mice(Olivares et al.,1993;Murphyand Tall,2016).In this context,recent studies have providedfascinating new insight into the regulatory mechanisms ofmonocytosis relevant to atherosclerosis(Figure 1).The role ofthe sympathetic nervous system(SNS)came to light as re-searchers sought to explain why atherosclerosis acceleratesafter myocardial infarction(MI).In the setting of an inflammatoryresponse,Ly6Chimonocytes initially give rise to macrophageson the inflammatory end of the inflammatory-resolution spec-trum,and as will be discussed in the following paragraphs,these macrophages promote atherosclerosis progression(Swir-ski et al.,2007).A substantial portion of Ly6Chimonocytes thatcontribute to atherosclerosis originate from the spleen,whichbecomes populated with bone-marrow-derived hematopoieticstem and progenitor cells(HSPCs)and carries out extramedul-lary hematopoiesis(Robbins et al.,2012).In this context,mousestudies suggest that a key mechanism of post-MI atheroscle-rosis is SNS-mediated release of HSPCs from the bone marrow,which leads to seeding of the spleen,elevated extramedullaryhematopoiesis,and increased release of Ly6Chimonocytes,which drive atherogenesis(Dutta et al.,2012).Further evidencesuggests that other stress-related events that are known to berisk factors for atherosclerotic disease,such as psychosocialstress,might work through a similar mechanism(Heidt et al.,2014).How these concepts apply to human atherothromboticvascular disease remains an important area for future study,particularly in view of uncertainties related to the functions ofCD14+monocytes in humans(Hilgendorf and Swirski,2012).Hypercholesterolemiaalsopromotesmonocytosis,particularlyLy6Chimonocytosis,in mice(Swirski et al.,2007),and defectivecholesterol efflux in HSPCs effected by genetic targeting ofcholesteroleffluxproteinscanalsoexacerbateLy6Chimonocyto-sis(MurphyandTall,2016)(Figure2).Themechanismresponsiblefor cholesterol-induced monocytosis involves expansion ofLin?cKit+Sca1+HSPCs in the marrow compartment(Murphyand Tall,2016).Mechanistic studies revealed that cholesterol-mediated changes in the plasma membrane of HSPCs lead toelevated cell-surface expression of the common b-subunit ofthe interleukin-3(IL-3)and granulocyte-monocyte colony-stimu-lating factor(GM-CSF)receptors and increased sensing of twoFigure 1.Regulation of Innate Immune Processes Related to Monocyte-Macrophages in AtherosclerosisLesionalmacrophagesoriginatefrombone-marrow-derivedhematopoieticstemandprogenitorcells(HSPCs),whichgiverisetocirculatingmonocytes.Incertaininstances,these stem cells first populate the spleen and then undergo extramedullary hematopoiesis.Proliferation and release of HSPCs can be exacerbated byelevated cellular cholesterol and by somatic mutations leading to clonal hematopoiesis,such as those that occur in aging and myeloproliferative disease(MPD).Thisprocesscanalsobestimulatedbystress-inducedactivationofthesympatheticnervoussystem(SNS).Themajorsubpopulationofmonocytesthatcontributeto atherosclerosis progression are Ly6chimonocytes,whichenter lesions in response to subendothelially retained apolipoprotein-B-containing lipoproteins(LPs)and subsequent chemokine release by activated endothelial cells.After differentiation into macrophages,these myeloid cells undergo a variety of phenotypicchanges under the influence of the factors listed in the figure.Those macrophages on the inflammatory end of the spectrum secrete proteins and carry outprocesses that promote atherosclerosis progression,whereas those on the resolution end of the spectrum promote lesion regression.622Immunity 47,October 17,2017ImmunityReviewkeyHSPCgrowthfactors,IL-3andGM-CSF(Yvan-Charvetetal.,2010).Thereisalsoevidencethathypercholesterolemia,presum-ably by increasing the cellular content of cholesterol,decreasesthe expression of Rb,a tumor suppressor that limits HSPC prolif-eration,andincreasestheexpression ofcyclinsB1,D1,andE1inHSPCs(Seijkens et al.,2014).Interestingly,when normocholes-terolemic recipient mice were transplanted with bone marrowfromeithernormocholesterolemicorhypercholesterolemicdonormice,the HSPCs of hypercholesterolemic donor origin showedincreased proliferation 10 weeks later(Seijkens et al.,2014).These data suggest a long-lived,cell-intrinsiceffect of hypercho-lesterolemiaonHSPCs,perhapsasaresultofepigeneticchangesin the donor HSPCs.Moreover,when Ldlr?/?mice were trans-plantedwithbonemarrowcellsfromhypercholesterolemicornor-mocholesterolemic mice and then fed a Western-type diet rich incholesterol and saturated fats,the mice that had received thathypercholesterolemic bone marrow developed larger and moreadvancedlesions.Thisincreaseinatherosclerosiswasaccompa-nied by a higher number of lesional leukocytes derived from thehypercholesterolemic mouse bone marrow cells and overall in-creases in plaque macrophages,granulocytes,and T cells.Other recent studies have taken advantage of the fact thatleukocytosis in myeloproliferative disease(MPD)is associatedwith atherothrombotic vascular disease(Murphy and Tall,2016).Forexample,aloss-of-functionpolymorphisminthegeneencod-ing a signaling adaptor protein called LNK(SH2B3)is associatedwithboth MPD and atherosclerosis(McMullinet al.,2011;Delou-kasetal.,2013).Moreover,somaticgain-of-functionmutationsinJAK2 kinase are also associated with MPD and atheroscleroticdisease(Viny and Levine,2014).Although processes related toneutrophilsandplateletsmostlikelycontributetothemechanismof this association,there is also a link to monocytosis.In thiscontext,genetic targeting of Lnk in Lnk?/?Ldlr?/?mice fed aWestern diet has been found to cause hypercholesterolemia-dependent monocytosis,which is associated with increasedamounts of the pro-atherogenic chemokine monocyte chemo-tactic protein-1(MCP-1;also known as CCL2)(Wang et al.,2016).Most importantly,these mice demonstrate increases inatherosclerotic lesion area,lesional macrophages,Ly6Chimono-cyteentryintolesions,andatherogenicplatelet-monocyteaggre-gates(Wangetal.,2016).Synergybetweenhypercholesterolemiaand LNK deficiency leads to further increases in IL-3-GM-CSFreceptor signaling in bone marrow HSPCs.Further insight intosome of these processes emerges from a study showing thatGlut1-mediated glucose uptake by inflammatory myeloid cellspromotes myeloproliferation in mice witheither defective choles-teroleffluxormyeloproliferativedisorders(Gautieretal.,2013).Inview of the link between glycolysis and inflammatory myeloid cellfunction(Van den Bossche et al.,2017),the authors propose thatGlut1-mediated glucose uptake provides the energy necessaryfor inflammatory myeloid cell proliferation.Ly6Clomonocytes derive fromLy6Chimonocytes and serve anendothelial maintenance patrolling function in the circulation,but their roles in tissues have become increasingly unclear,andit is not even certain whether they differentiate into macrophages(Jakubzick et al.,2017).As such,the role of Ly6Clomonocytes inFigure 2.Intracellular Atherosclerosis-Influencing Effects of Excess Cholesterol on Myeloid Cells and T CellsIn the setting of hypercholesterolemia or defects in cholesterol efflux,HSPCs accumulate excess cholesterol.The consequence is enhanced IL-3 and GM-CSFgrowth factor signaling,leading to HSPC proliferation and monocytosis.With aging,clonal hematopoiesis can occur as a result of loss-of-function mutations in anumber of genes,including TET2.This process might also contribute to monocytosis.Monocytosis is associated with increased accumulation of inflammatorymonocyte-derived macrophages in atherosclerotic lesions and a higher risk of atherosclerotic vascular disease in humans.These lesional macrophages are alsosubject to intracellular cholesterol accumulation because of their internalization of subendothelial apoB LPs.Excess cholesterol in macrophages has multipleeffects that enhancelesioninflammation,including activation oftoll-likereceptors(TLRs)and inflammasomes.Theresultis increasedproductionof inflammatorychemokines and cytokines,including inflammasome-derived IL-1b and IL-1b-induced IL-6.Moreover,changes associated with clonal hematopoiesis,e.g.,lossof TET2 function,can also activate the inflammasome in macrophages,further fueling lesional inflammation.T cells do not have the capacity to accumulate largeamounts of excess cholesterol,but several studies have shown that perturbations of T cell cholesterol metabolism can affect T cell differentiation and activation.Impaired ABCG1 cholesterol efflux from T cells results in enhanced Treg differentiation,which reduces atherosclerotic lesion development and inflammation.Incontrast,impaired esterification of cholesterol by deficiency or inhibition of acyl-coenzyme A:cholesterol acyltransferase increases the formation of lipid rafts inCD8+effector T cells and thereby enhances immune synapse formation and killing functions of these cells.The net effect of increases in T cell cholesterol onlesion development and inflammation are likely to reflect chang