Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

Godfrey S. Getz

doi:10.1194/jlr.r400013-jlr200

Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

Getz, Godfrey S. 2005-01-01 00:00:00 thematic review Thematic review series: The Immune System and Atherogenesis Immune function in atherogenesis Godfrey S. Getz Department of Pathology, Biochemistry, and Molecular Biology, University of Chicago, Chicago, IL Abstract In this overview to a new thematic series on the nisms. I will then update the information based upon immune system and atherogenesis, I provide a very brief studies published in the last 2–3 years. This will provide summary of current conceptions of atherogenesis, of the in- the backdrop for an introduction to this Thematic Series. nate and adaptive immune systems, and of the participation The overview will conclude with a set of additional com- of the latter in atherogenesis, with particular emphasis on ments that might be helpful in the consideration of im- studies of the involvement of the immune system in athero- mune system participation in the modulation of athero- sclerosis reported in the last 2 years. This is followed by a sclerosis. short outline of the eight reviews that will make up this the- matic series. The overview is concluded with some cave- ats that should be considered in the analysis of atheroscle- rosis in experimental animals.—Getz, G. S. The immune ATHEROSCLEROSIS AS CHRONIC INFLAMMATION system in atherogenesis. J. Lipid Res. 2005. 46: 1–10. It is now widely recognized that atherosclerosis is a spe- Supplementary key words innate immunity • adaptive immunity • cyto- ciﬁc example of a chronic inﬂammatory response mainly kines to dyslipidemia and other risk factors. This notion was ar- ticulated in an excellent article by Russell Ross (5). In keeping with this formulation, the atherosclerotic plaque This issue inaugurates a new Thematic Series that high- has as its major components macrophages, cells of the lights the role of immune function in atherosclerosis. To adaptive immune system, smooth muscle cells, and matrix quote from an earlier editorial inaugurating another The- components. As with most chronic inﬂammatory reac- matic Series: “the complexities of lipid and lipoprotein tions, the cells of the immune system have the potential to metabolism, and the differing responses of vascular wall signiﬁcantly inﬂuence the outcome of the inﬂammation. cells (including immune cells) to the interplay of lipopro- The atherosclerotic plaque is notable for its focal nature, teins and to the vast array of circulating cellular and blood being mostly encountered in regions of the macrovascula- elements, are enormous” (1). This viewpoint can be ap- ture subject to disturbed ﬂow hemodynamics. plied also to the interaction of the components of the im- In both human and experimental atherosclerosis, hy- mune system with lipid and lipoprotein metabolism in the percholesterolemia is the major exciting factor for the de- context of the evolution of the atherosclerotic plaque. velopment of vascular lesions. The increased cholesterol is A modern approach to the molecular pathogenesis of carried either by LDL or VLDL remnants. It is now atherosclerosis has been well reviewed (2). The role of in- thought that increased plasma levels of LDL result in en- nate and adaptive immunity in its pathogenesis has been hanced oxidation or perhaps other modiﬁcations of LDL comprehensively dealt with in two recent reviews (3, 4). within the vascular wall, representing a major initiating Readers are encouraged to consult each of these reviews agent for the formation of the atherosclerotic response. alongside of this overview. Lipoproteins retained in the vessel wall by matrix compo- Because the following series deals in depth with impor- tant aspects of immune function in relation to atheroscle- rosis, in this overview I will brieﬂy summarize the state of the subject, mostly as reﬂected in these aforementioned Abbreviations: apoE, apolipoprotein E; CD40L, CD40 ligand; CRP, three reviews. Here, the focus will be on the lesion out- C-reactive protein; dn, dominant negative; IL, interleukin; MHC, ma- come, without dealing with the detailed cellular mecha- jor histocompatibility complex; NF-B, nuclear factor B; NK, natural killer; NK-T, natural killer T; OxLDL, oxidized low density lipoprotein; RAG, recombination-activating gene; SAA, serum amyloid A; TCR, T-cell receptor; TGF, transforming growth factor; Th cell, T-helper cell; TNF, Manuscript received 2 November 2004. tumor necrosis factor. To whom correspondence should be addressed. Published, JLR Papers in Press, November 16, 2004. DOI 10.1194/jlr.R400013-JLR200 e-mail: [email protected] Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 46, 2005 1 This is an Open Access article under the CC BY license. nents, the most prominent of which are the proteogly- BRIEF SUMMARY OF THE IMMUNE SYSTEM cans, are probably especially susceptible to oxidation. Oxi- dation of retained lipoproteins may be a function of the The immune system has been recognized as an impor- production of reactive oxygen species generated by the tant component of atherosclerotic inﬂammation. The im- mune system can be thought of as two subsystems, the in- cells of inﬂammatory inﬁltrates or by enzymes such as li- nate immune system and the adaptive immune system. poxygenases produced by inﬁltrating macrophages. Mac- rophages import oxidized LDL (OxLDL) into the endoso- The innate immune system is critical to the initial inﬂam- mal system via a variety of scavenger-type receptors. The matory response. Several cellular and mediator responses are involved. The acute cellular response in the context of cholesterol so imported ultimately ends up in the cyto- atherosclerosis is centered on the monocyte-macrophage, plasm, where it is esteriﬁed, generating cholesteryl ester droplets and forming foam cells that are the hallmark of whose participation has been summarized above. Other early and growing atherosclerotic plaques. The accumula- cells may also play some role. This includes natural killer (NK) cells, dendritic cells, mast cells, and B1 cells. NK tion of such foam cells constitutes the bulk of the early cells, as the name implies, are able to kill tumor cells, vi- vascular lesion, designated by some as a fatty xanthoma (6). Oxidized phospholipid moieties of oxidized lipopro- rally infected cells, or antibody-coated cells. But they also teins signal to many of the cells in the evolving plaque, es- secrete cytokines, the most prominent of which is IFN-. NK cells when activated are particularly efﬁcient produc- pecially to the endothelium overlying the accumulating ers of IFN-, which activates macrophages (8). NK cell ac- OxLDL and to foam cells. Among other responses, this sig- naling increases the expression of adhesion molecules that tivity is inﬂuenced by other cytokines, such as IL-2, IL-15, facilitate the homing of monocytes and lymphocytes to and IL-12. Dendritic cells play a key role in antigen pre- sentation, expressing high levels of scavenger receptors this localized activated endothelium. The foam cells and and class II major histocompatibility complexes (MHCs), activated endothelium may also produce proinﬂamma- tory cytokines such as interleukin-1 (IL-1), IL-6, IFN-, which present antigens to cells of the adaptive immune and tumor necrosis factor- (TNF-) (7), which promote system. They also express costimulatory molecules, B7-1 and B7-2. Mast cells on activation release histamine, leuko- the further development of the inﬂammatory response. trienes, platelet-activating factor, proteases, and cytokines. Also, the elaboration of chemotactic factors such as MCP-1 attracts the further inﬂux of monocytes. The macrophage In a sense, all of the cells included in the initial atheroscle- foam cell is a very versatile multifunctional cell, capable of rotic response can be regarded as part of the innate im- mune response, because endothelial cells and smooth elaborating reactive oxygen species, prostaglandins, nitric muscle cells can be induced, for example by IFN-, to ex- oxide, and growth factors. Foam cell homeostasis is the re- sult of new recruitment and lipid loading on the one hand press class I and class II MHC proteins. The MHCs on and efﬂux of lipid on the other. The latter is promoted by these cells are capable of presenting antigens, although not nearly with the efﬁciency of the more traditional anti- apolipoprotein E (apoE), apoA-I, HDL, and the ATP bind- gen-presenting cells, macrophages, and dendritic cells. B1 ing cassette proteins ABCA1, ABCG1, and ABCG4. The progression of the lesion from the fatty xanthoma cells bridge the innate and adaptive immune systems. They to a more complex lesion is characterized by the migra- are responsible for the production of IgM antibodies, many of which react with oxidized phospholipids. These tion of smooth muscle cells from the media into the sub- antibodies have been shown to block the uptake of Ox- endothelial intima and their subsequent proliferation. This is mediated, in part, by the growth factors secreted LDL by macrophage scavenger receptors. The activation from macrophage foam cells. These smooth muscle cells of the inﬂammatory response induces the synthesis and release of IL-1, TNF-, and IL-6, which are responsible for may themselves become foam cells, but more importantly inducing in the liver the transcription of the acute-phase they are responsible for the synthesis of matrix proteins and proteoglycans. The foam cells may ultimately die ei- plasma proteins, including C-reactive protein (CRP), se- ther by necrosis or apoptosis, liberating their contained rum amyloid A (SAA), ﬁbrinogen, and ferritin, as well as proteins of the complement system. An outline of the in- lipid and producing a necrotic core with extracellular nate immune system is shown in Fig. 1. lipid. The death of foam cells is probably related to the dysregulation of intracellular lipid metabolism and the The adaptive immune system (Fig. 2) reacts to endoge- formation of cytotoxic oxidized sterols and other lipids. nous neoantigens (e.g., apoptotic cells or OxLDL) or ex- ogenous antigens, resulting in the activation of T-cells and Late atherosclerotic plaques may also undergo cartilagi- B-cells. Some of these neoantigens are also targets of the nous dysplasia with calcium deposition. The increase in the size of the evolving atherosclerotic plaque arises from innate immune system. The adaptive immune system may the continued recruitment of monocytes and lymphocytes, inﬂuence atherosclerosis in one of three ways: 1) by cell- cell interaction (e.g., between antigen-presenting cells, the continued migration and proliferation of smooth macrophages, B-cells, or dendritic cells) and T-cells; 2) by muscle cells, the evolution of a necrotic core, and matrix protein synthesis. Activation of the macrophages in the le- the secretion of a variety of cytokines from activated T-cells, sions, particularly on the lesion shoulders, may lead to the which mediate an activation of macrophages and other cells of the atherosclerotic plaque; or 3) by the produc- release of proteases, with disruption of the plaque sur face tion of antibodies by B-cells in a T-cell-dependent or -inde- giving rise to the unstable plaque lesion becoming the ni- dus for thrombosis and consequent clinical complications. pendent manner. Some of these antibodies have the ability 2 Journal of Lipid Research Volume 46, 2005 Fig. 2. Adaptive immunity. This network is activated by exposure to either neoantigens such as OxLDL and heat shock proteins (hsps) or exogenous antigens such as chlamydial antigens. These antigens are processed and presented by antigen-presenting cells (dendritic cells, macrophages, or B-cells) in the context of major histocompatibility complex (MHC) class I or II or CD1 for den- dritic cells and macrophages and the B-cell receptor in the case of Fig. 1. Innate immunity. The liver produces the major actor in B-cells. The antigen-presenting cells present antigen to CD4 T-cells atherogenesis in the form of VLDL, which in transit through the bearing cognate T-cell receptors, resulting in activation of the T-cells plasma is converted to LDL. Some of the LDL enters the subendo- but only in the presence of the second signal produced by costimu- thelial space, where it may be oxidized, forming oxidized LDL (Ox- latory molecules (e.g., B7-1, B7-2) interacting with CD28. B-cells ac- LDL). The liver in a proinﬂammatory state [i.e., increased cyto- tivated by antigens may also interact with T-cells via the CD40-CD40 kines interleukin-1 (IL-1), IL-6, and tumor necrosis factor- (TNF-)] ligand (CD40L) pair of costimulatory molecules predominantly in- also produces many acute phase proteins, some of which are listed. volved in this interaction but also in other cell-cell interactions. The Their direct participation in the process of atherogenesis is not yet activated and selected T-cells may differentiate into T-helper cell 1 clear. Components of the OxLDL elicit the activation of endothe- (Th1) or Th2 subsets, producing predominantly IFN- and IL-4, re- lial cells, resulting in the upregulation of adhesion molecules, spectively. IFN- may positively feed back on the activity of the anti- which facilitate the entry of blood monocytes into the subendothe- gen-presenting cells, whereas IL-4 facilitates the differentiation of lial space. Here, monocytes may be converted to macrophages ex- B-cells into antibody-producing cells. The third subset of CD4 pressing cell surface scavenger receptors, which mediate the im- cells are the natural killer T (NK-T) cells, which most often see lipid port of OxLDL, which contains the cholesterol that is stored in the antigen in the setting of CD1 on dendritic cells or macrophages. cell as cholesteryl ester (CE), forming the droplets characteristic of NK-T cells, unlike most of the other CD4 T-cells, may produce the foam cell of the evolving lesion. The monocyte macrophage is a both IFN- and IL-4. The B-cells produce antibodies of the IgM or multipotential cell, and some of its secreted products are listed. IgG types that interact with the antigens of modiﬁed LDL or other These products inﬂuence the evolution of the plaque, the autoacti- relevant antigens. This ﬁgure is modiﬁed by permission from the vation of the inﬂammatory reaction, and the migration of smooth ﬁgure in Hansson et al. (4). muscle cells to the subendothelial space, where they contribute to lesion evolution. Natural killer (NK) cells may also enter the suben- dothelial space and produce many cytokines or chemokines, but on their surface in the context of MHC class I or II mole- mostly IFN-, which among other actions activates the monocyte cules. Such antigenic epitopes interact with cognate T-cell macrophage. The B1 cell, which is not present in the lesion, receptors (TCRs) on the surface of T-cells, which respond bridges the innate and adaptive immune systems and may produce either by anergy or activation. The decision between these IgM antibodies that inhibit the uptake of OxLDL into the macro- phage, slowing its conversion to a foam cell. CRP, C-reactive pro- responses is largely determined by the availability of co- tein; MCP1, monocyte chemotactic protein 1; PDGF, platelet de- stimulatory molecules (e.g., B7-1 or B7-2) on antigen-pre- rived growth factors; SAA, serum amyloid A; SMC, smooth muscle senting cells that interact with CD28 on T-cells. The pool cells; TGF, transforming growth factor. of individual TCRs is enormous, arising during T-cell de- velopment as a result of gene rearrangements involving to block the import of modiﬁed lipoproteins via macro- many genes, including the obligatory recombination-acti- vating genes (RAG 1 and 2). The bulk of the T-cells ex- phage scavenger receptors. press the TCR consisting of a heterodimer of and chains. Antigenic molecules are processed within the endoso- A small proportion of T-cells express a TCR consisting of mal system of antigen-presenting cells and are presented Getz Immune function in atherogenesis 3 and subunits. The latter T-cells recognize antigens with- differences both in the distribution of lesions (e.g., aortic out the necessity that they be presented on MHC mole- root dominance in the mouse) and in the quality of the le- cules. Although these cells are capable of generating a sions. large variety of antigen receptors, most of them recognize Several lines of evidence have been adduced to impli- a limited number of antigens (9). Some of these cells re- cate the immune system in the process of atherosclerosis. spond to heat shock proteins (10). First, the presence of immune cells and immune cell T-cells may be divided into CD4 and CD8 subclasses. products in the human and/or experimental atheroscle- The majority of T-cells in atherosclerotic plaques are CD4 rotic lesion is taken to indicate their likely participation in cells, although smaller numbers of CD8 cells have been the lesion biology. Millonig, Malcom, and Wick (12) have detected. CD4 cells recognize antigen loaded on MHC described a “vascular associated lymphoid tissue” in vascu- class II molecules of the antigen-presenting cell, whereas lar regions susceptible to atherosclerosis. Macrophages and CD8 cells recognize antigens presented in the context T-cells are detectable in this tissue even before the plaque of MHC class I molecules. Among the CD4 cells are sev- develops. Among the immune cells and molecules de- eral subgroups, three of which have been investigated in tected in human atherosclerotic plaques are macrophages, murine atherosclerosis. These subgroups are distinguished dendritic cells (13), CD4 T-cells, CD8 T-cells, MHC by the complement of cytokines they produce. Th1 cells class II, CD40, and CD40L, the cytokines IL-1, IL-2, IFN-, mainly secrete proinﬂammatory cytokines such as IFN-, IL-7, IL-10, IL-12, IL-18, TNF-, transforming growth fac- which activates macrophages and facilitates the produc- tor- (TGF), as well as immunoglobulin (4, 12). The cy- tion of antibodies of the IgG2a class by B-cells. T-helper 1 tokines of Th2 cells are present at much lower levels (7). (Th1) cells do not secrete IL-4 or IL-5. Th2 cells, on the The presence of both proinﬂammatory and anti-inﬂam- other hand, secrete IL-4 and IL-5 but not IFN-. These matory cytokines speaks to the possibility of the coexistence cells provide help for the synthesis of other antibody of proatherogenic and antiatherogenic inﬂuences in le- classes. The Th2 cytokines may be anti-inﬂammatory. There sions. B-cells are relatively rare among the cells of the hu- is cross-regulation among these two subsets of T-cells, so man atherosclerotic plaque, although they may be found that each tends to inhibit the other. IFN- inhibits Th2 in the neighboring adventitia. cells and IL-4 inhibits Th1 cell cytokine secretion. Also, Second, more compelling evidence for the role of the IL-10 inhibits the Th1 pathway, whereas IL-12 reduces the immune system in atherogenesis derives from speciﬁc Th2 responses (4). A third special subset of T-cells are the gene deletion or overexpression in mice. The knockout of natural killer T cells (NK-T cells), which bear some of scavenger receptors (SR-A, CD36), mediators of monocyte the same markers as NK cells, but unlike the latter they ex- chemotaxis (MCP-1, CCR ), IFN- or its receptor, costimu- press rearranged cell surface TCRs of limited diversity. latory molecules, CD40L, and the RAG genes, resulting in They mainly recognize lipid antigen in the context of the global immunodeﬁciency, all lead to a reduction in ath- MHC-like compound CD1. There are other T-cell subsets erosclerosis in mouse models (3, 4). On the other hand, that have been less studied in atherosclerosis (e.g., T-regu- the knockout of the Th1 inhibitory cytokine, IL-10, results latory cells, Th3 cells, etc.). in an increase in lesions. The pattern of cell and cytokine B-cells are the other major group of circulating lympho- involvement suggests a Th1 dominance in atherosclerotic cytes. They recognize antigen via the B-cell antigen recep- lesions. This dominance has been reported to reverse in tor, in which cell surface IgM plays a central role. Like T-cells, the face of marked hypercholesterolemia, at least in the B-cells, through these receptors, express unique speciﬁc- apoE-deﬁcient mouse (14). The Th2 cytokine IL-4 was ity derived from the rearrangement of immunoglobulin thought to afford protection, but its inﬂuence may be genes, a process that is also RAG dependent. Mature B-cells, more complex, because IL-4 deﬁciency in the background designated as plasma cells, secrete speciﬁc antibodies. of either apoE deﬁciency or LDL receptor deﬁciency leads The production of antibodies to protein antigen requires to a reduction in lesion size (15, 16). This argues that cyto- T-cell help. The interaction between T-cells and B-cells is fa- kine effects might not be simply explained by resorting to cilitated by CD40 ligand (CD40L) expressed on T-cells the Th1/Th2 paradigm. Non-T-cell-dependent effects of and CD40 on B-cells. IL-4 may be at work (16). Recently, IL-5 has been reported to play a protective role (17). Cytokine effects on athero- genesis indeed seem to be quite complex. The knockout of immunoglobin results in a B-cell deﬁciency. Trans- IMMUNE MODULATION OF ATHEROSCLEROSIS plantation of bone marrow cells from B-cell-deﬁcient mice This topic is studied in both human atherosclerosis and into LDL-deﬁcient mice results in an increase in athero- experimental models of atherosclerosis, with the mouse sclerosis (18). This indicates that B-cells may have a pro- now holding pride of place because of the capacity to ma- tective effect on atherosclerosis, despite their relatively nipulate almost at will its genetic program. Indeed, differ- rare appearance within the plaque. This suggests that ent strains of mice exhibit quite different susceptibilities their effects may be mediated by the antibodies they se- to atherosclerosis (11), indicating the importance of ge- crete, or perhaps by some other immunoregulatory role. netic modiﬁers in the evolution of the atherosclerotic le- A third basis for implicating the immune system in sion. The murine lesion bears many similarities to the hu- atherogenesis is provided by the direct transfer of immu- man lesion, but it is worth noting that there are some nological mediators. IFN-, IL-12, or IL-18 injection all in- 4 Journal of Lipid Research Volume 46, 2005 crease atherosclerosis (3). The administration of antibod- tor and lysophosphatidic acid, which are likely to be en- ies to CD40L reduces lesion formation in LDL receptor- riched in progressing lesions. deﬁcient mice, whereas the use of antibodies to TGF in the apoE-deﬁcient mouse increases atherosclerosis, em- phasizing the atheroprotective inﬂuence of this cytokine. ADAPTIVE IMMUNITY The fourth type of evidence directing attention to the role of the immune system involves immune cell transfer With respect to the adaptive immune system, NK-T cells or vaccination. When CD4 cells from apoE-deﬁcient mice have entered the atherosclerosis arena. As they recognize in which the Th1 cell subtype is dominant are transferred lipid antigen in the context of CD1, their involvement is to immunodeﬁcient apoE-deﬁcient mice, an increase in worthy of consideration. Their activation increases athero- atherosclerosis is noted (19). On the other hand, the sclerosis in the apoE-deﬁcient model (28). It has recently transfer of B-cells from apoE-deﬁcient mice with or with- been shown that regulatory T-cell subtype 1 upon transfer out T-cells reduces atherosclerosis (20). The two major an- to apoE-deﬁcient mice reduces atherosclerosis. This is as- tigens to which autoantibodies are detected are OxLDL sociated with a reduction in the IFN--to-IL-10 ratio (29). and heat shock proteins. Vaccination with the former de- The role of costimulatory molecules has been empha- creases lesion formation, whereas in the case of the latter, sized recently (30). It has been known for some time that atherosclerosis is increased (3). the CD40-CD40L interaction is implicated in atheroscle- In the last 18–24 months (i.e., since the publication of rosis (31). These molecules are members of the TNF su- the two reviews brieﬂy summarized above), many addi- perfamily. An alternative name for CD40 is TNF receptor tional studies have been published that bear on the topic superfamily 5 (TNFRSF 5), and the CD40 is designated of this overview. TNFSF 5 (31, 32). Although the expression of this pair was thought to be restricted to B-cells, dendritic cells, and activated T-cells, it is now clear that they are more widely expressed in the cells present in atherosclerotic plaques. INNATE IMMUNITY Interdiction of their interaction results in a reduction in lesion development, while also modifying the composition In relation to the innate immunity network, the poten- of the lesion toward a less inﬂammatory and more ﬁbro- tial proatherogenic role of NK cells has received renewed genic lesion phenotype (31). Another pair of costimula- attention (21, 22). Dendritic cells seem to be concentrated tory molecules that belong to the TNF superfamily is in the rupture-prone areas of vulnerable human carotid LIGHT (TNFSF 14) (32) and its receptor, either HVEM artery plaques (23). There has of course been continued (TNFRSF 14) expressed on lymphocytes and NK cells or study of CRP and its role as a marker of or a participant in lymphotoxin expressed on stromal cells and monocytes atherosclerosis. The involvement of the Toll-like receptors (33). These molecules have been noted in human athero- in signaling and the initiation of atherosclerosis has also sclerotic plaques clustered in macrophage-rich regions, been studied recently. Among the hepatic products that and their properties suggest that their interaction is proin- participate in the anti-inﬂammatory response is the com- ﬂammatory (34, 35). The other costimulatory pair is B7-1 plement system, which can be activated by CRP (24). The (CD80) and B7-2 (CD86). They are members of the im- complement peptides C3a and C5a may be chemotactic munoglobulin superfamily, are expressed in antigen-pre- for monocytes. The lack of complement component 5 in senting cells, and bind to CD28 on resting T-cells. B7-1 and apoE-deﬁcient mice apparently has little impact on ath- B7-2 overlap in function. When their coupled absence is erosclerosis. On the other hand, C3 deﬁciency studied in combined with LDL receptor deﬁciency, atherosclerosis is the model that is lacking both apoE and the LDL receptor reduced and the lesions have fewer T-cells, smooth muscle resulted in an increase in aortic lesions, although cross- cells, and less collagen (36). Thus, like the other pairs of sectional analyses of the aortic root showed no difference costimulatory molecules, they are proinﬂammatory. in the size of the lesions (25). The C3-deﬁcient mice had increased triglyceride and LDL cholesterol levels. Aortic atherosclerosis in C3-deﬁcient mice crossed with the LDL receptor-deﬁcient model was also increased (26). CYTOKINES Most of the emphasis in atherogenesis has been on the recruitment of monocytes into the lesion-prone areas, As described above, cytokines play important roles in where they become macrophage foam cells. The fact that modulating atherosclerosis. Lymphotoxin also func- lesions regress, leaving fewer macrophages, implies that tions as a proinﬂammatory cytokine in murine atheroscle- these cells must have the capacity to migrate out of the le- rosis (37). Either the absence of IL-1 or a reduced gene sion. In an elegant transplant model, Llodra and col- dosage of IL-1 receptor antagonist in the apoE-deﬁcient leagues (27) have demonstrated the outward migration of background suggests an inﬂuence of IL-1 in promoting macrophages and dendritic cells from the lesion-ﬁlled atherogenic cell signaling (38, 39). The larger lesions of aortic arch of an apoE-deﬁcient mouse when the arch was the IL-1 receptor antagonist-deﬁcient mice are enriched transplanted into a wild-type mouse. The migration ap- in macrophages relative to smooth muscle cells. pears to be limited by lipids, such as platelet-activating fac- Information on the role of the proinﬂammatory cyto- Getz Immune function in atherogenesis 5 kine IFN- produced mainly by Th1 and NK cells has been are signiﬁcantly distinct, so that further investigation is re- extended in several experiments. The knockout of IFN- quired to resolve the discrepancy. in the LDL receptor-deﬁcient background substantially re- duced lesion size in several regions of the aorta, with a rel- ative loss of macrophages and smooth muscle cells in the THIS SERIES early lesions (40). IFN-, which has previously been re- ported to downregulate the SRA and CD36 scavenger recep- There will be eight substantial reviews in this series, all tors, is thought to be important for the uptake of modiﬁed of which deal with currently active topics. Four of these will be devoted largely to the innate immune system, and lipoproteins and foam cell formation. IFN- has now been the others will deal with the bridge between innate immu- shown to upregulate another scavenger receptor, SR-PSOX, which recognizes phosphatidylserine and OxLDL. SR-PSOX nity and the adaptive immune response. Because macro- is identical to the transmembrane protein CXCL16, a che- phages are the hallmark of the atherosclerotic lesion, they will be heavily represented in at least half of the reviews. mokine receptor involved in T-cell migration. SR-PSOX The ﬁrst of these will be devoted to the increasing variety and its receptor are present in atherosclerotic lesions (41). The dominance of Th1 and their secreted products of scavenger receptors expressed on the macrophage and within the plaque is balanced by counterinﬂammatory in- dendritic cell surfaces. David Greaves and Siamon Gor- don will discuss how these receptors might be involved in ﬂuences, mediated in part by IL-10, expressed in macro- atherogenesis, but they will also address other aspects of phages and Th2 lymphocytes in the plaque. When LDL receptor-deﬁcient mice are transplanted with bone mar- the biology of these receptors. This review will be followed row overexpressing IL-10 in T-cells, atherosclerosis is re- by an overview of the currently very active ﬁeld of the role of acute phase proteins, such as CRP, SAA, and other duced (42). In contrast, the transplantation of IL-10-deﬁ- members of this family. This will be reviewed by Alan cient bone marrow into LDL receptor-deﬁcient mice led to a marked increase in lesion development at several Chait, Jack Oram, and Jay Heinecke. One of the major is- sites, and these lesions were rich in macrophages and lym- sues to be addressed relates to the possibility that these proteins are directly involved in atherosclerosis, rather phocytes (43). Nuclear factor B (NF-B) mediates many than “simply” serving as markers of the inﬂammatory proinﬂammatory effects. The recent observation that se- lective attenuation of NF-B signaling in macrophages re- state. Much work has been done on the possible proat- sults in an increase in atherosclerosis in the LDL receptor- herogenic inﬂuence of microorganisms such as Chlamydia. The recognition of the cell surface molecules of these or- deﬁcient background is somewhat surprising (44). This ganisms is via the so-called Toll-like receptors, which are could be attributed to the substantial reduction in IL-10 production. A most interesting recent ﬁnding hypothe- expressed on such cells as macrophages, neutrophils, NK sizes that IL-5 inﬂuences the stimulation of the produc- cells, dendritic cells, and endothelial cells. These recep- tors may signal to the transcriptional machinery of the cell tion of anti-oxidized phosphatidylcholine antibodies after to promote a proinﬂammatory state. There are at least 10 immunization with malondialdehyde LDL (17). The im- munization caused a preferential expansion of cognate such receptors with differing speciﬁcity and cell distribu- Th2 cells that secrete IL-5, which then stimulates B1 cells. tion. Recent papers have implicated some of these recep- tors in atherogenesis (50, 51). This subject will be re- This provides a link between natural and adaptive immu- viewed by Linda Curtiss. nity and will be fully discussed in the thematic review by Binder, Witztum, and colleagues on natural antibodies. I will then comment on the bridge between innate and The atheroprotective cytokine TGF has also received adaptive immunity in an extended editorial. This will be followed by a review of the natural antibodies recognizing considerable attention. It functions as an anti-inﬂamma- modiﬁed lipoproteins and apoptotic cells as well as mole- tory cytokine, limiting the recruitment of leukocytes and promoting the synthesis of collagen and extracellular ma- cules that mimic these antigens. This is an exciting ﬁeld trix (45, 46). TGF-deﬁcient mice die early, so alternative with continuing surprises pointing in new directions of substantial potential clinical signiﬁcance. The recent ob- strategies are used to attenuate its function. Most have used servations in this area will be reviewed by Peter Shaw, Chris- either a soluble TGF receptor that inhibits signaling (47) or a dominant negative (dn) mutant receptor driven by a toph Binder, and Joseph Witztum and colleagues, who have T-cell-speciﬁc promoter (CD2 or CD4) expressed as a trans- contributed greatly to this ﬁeld. As mentioned above, a number of lymphocyte sub- gene (48, 49). These studies noted some similarities and classes have come into sharp focus as inﬂuencing athero- some discrepancies. In the Robertson study (48), T-cell dn receptor-expressing mice were crossed with apoE-deﬁ- genesis. This includes B1 cells, NK cells, and NK-T cells. cient mice, whereas in the Gojova study (49), bone mar- These unusual suspects as well as dendritic cells and their contribution to atherogenesis will be reviewed by Cath- row was transplanted from dn TGF receptor-expressing erine Reardon and Paul VanderLaan. mice into LDL receptor-deﬁcient mice. Both groups of in- vestigators noted lesions that exhibited increased T-cells, It is clear from the above overview that the atheroscle- macrophages, and reduced collagen, an inﬂammatory rotic plaque is a “soup” of cytokines, produced by many cell types within the inﬂammatory plaque and acting upon phenotype. The Robertson study noted increased lesion many of their neighbors. Knockout experiments and other size, whereas a modest reduction in aortic root lesions was noted in the Gojova study. These experimented models manipulation of expression levels of these molecules clearly 6 Journal of Lipid Research Volume 46, 2005 demonstrate their inﬂuence on the atherogenic process. to the lesion phenotype or detailed morphology. In model- We have asked Elaine Raines and Alan Daugherty to focus ing lesions of clinical relevance, the quality and composition our attention on the role of these cytokines on target cells of the lesion is probably of more importance. In accepting within the plaque. Elaine Raines will do this for endothe- the general view of the mechanisms of atherogenesis, one lial cells and smooth muscle cells. Alan Daugherty will in- should bear in mind the potential limitations in the evi- form us about the macrophage and leukocytes as targets. dence that supports this view. We will conclude the series by a return to the central Some interventions have modest effects on the size of role of the monocyte, which must be recruited into the the lesion but do inﬂuence the lesion phenotype. This is evolving lesion to fulﬁll its critical participation. Thus, Os- exempliﬁed in recent murine atherosclerosis studies on wald Quehenberger will review monocyte chemotaxis and IFN- deﬁciency in atherosclerosis in the LDL receptor- atherogenesis. deﬁcient mouse (40). Lesion phenotype is dramatically changed with modulation of IL-10 signaling and attenua- tion or alteration of TGF signaling (42, 43, 47, 49). We have previously drawn attention to the differential ADDITIONAL COMMENTS responses of various vascular regions to immune modula- In summary, the prevailing evidence suggests that ath- tion (52). We suggest that this is attributable to the way re- erosclerosis progression represents a chronic inﬂammatory gional differences in hemodynamic proﬁles prime the en- reaction involving the participation of the innate immune dothelial phenotype to respond to such modulations. An system and modulated by the adaptive immune system. In alternative explanation could be that differences in the the latter case, the proinﬂammatory pattern dominates as microenvironment in the subintimal space in which le- a result of Th1 cells secreting IFN-, a situation stimulated sions develop condition the atherosclerotic response. We by IL-12 and IL-18. However, it seems clear that develop- have seen this in comparing the response of the aortic ing atherosclerotic plaques represent a balance between root and the innominate artery to immune deﬁciency in proinﬂammatory and anti-inﬂammatory inﬂuences, with the LDL receptor-deﬁcient model (53). Other examples the former being dominant during early plaque evolu- of the differential response of aortic regions to immune tion. That there are anti-inﬂammatory inﬂuences at work modulators include IL-4 deﬁciency combined with LDL is indicated by the experimental manipulation of IL-4, IL-10, receptor deﬁciency, in which there was no impact on the and TGF as discussed above. Also, B-cells and their se- aortic root lesion size but substantially reduced lesion size creted antibodies recognizing relevant antigens may con- in the aortic arch and thoracic aorta (15). A second exam- tribute to some degree of atheroprotection. However, the ple involves immunization of LDL receptor-deﬁcient mice adaptive immune system is not required for the develop- with OxLDL, which reduced aortic root lesion size but ment of atherosclerosis. Quite substantial lesions develop had no inﬂuence on lesions in the remainder of the aorta in the absence of mature T- and B-cells in mouse models (54). The majority of studies of atherosclerosis in the in which the function of the RAG gene(s) is eliminated. mouse have examined lesions in the aortic root or in the Our current conception of experimental atherosclero- whole aorta by en face analysis. Given the hitherto re- sis derives predominantly from a limited examination of ported differences in response according to the vascular atherosclerosis either by the measurement of aortic root region examined, it seems that our understanding of the lesions, not a characteristic site for human atherosclerosis, interplay of the immune system on murine atherosclerosis or en face measurement of the extent of aortic lipid le- would be greatly enhanced by measuring the atheroscle- sions. Sometimes both methods are used. This examina- rosis response at more than one vascular site. A dramatic tion may be undertaken early in atherosclerosis, when the example of such a difference is shown by the surprising in- predominant lesion is a fatty streak (xanthoma), or later, crease in abdominal aortic atherosclerosis seen in female when more complex lesions are seen. It should not be a apoE-deﬁcient mice also lacking CD4 cells (55). surprise that inﬂuences on early lesions and more complex It is well known that mouse strains differ in their suscep- lesions may differ. In the early lesion, composed mostly of tibility to atherosclerosis, with the C57BL/6 strain being foam cells, the cellular composition is reasonably homoge- the most sensitive. Many of the earlier experiments used neous. On the other hand, as the lesion increases in com- mouse strains that were not fully backcrossed into this ge- plexity, the potential for cellular interactions may be very netic background. Often, strain 129 was originally used different. The microarchitecture of the lesion, with the for the generation of the knockout mice. This was the case stromal separation of clusters of cells of different func- for the knockout of the RAG genes. The initial work on tion, could inﬂuence the measured outcome of an inter- the apoE-deﬁcient strains lacking the RAG genes used an- vention. Seldom does a single investigator examine lesions imals of modestly mixed background (56–58). We have at two different times, and this can be misleading, because shown that the effect of immune deﬁciency on innomi- the selection of a particular time point as readout may nate artery atherosclerosis in LDL receptor-deﬁcient mice bias the results in a lesion that evolves over time. For exam- is quite sensitive to the genetic background (53). An inter- ple, in apoE/IL-12-deﬁcient mice, lesion area is reduced esting illustration of this complexity is shown in studies of at 30 weeks of age but not at 45 weeks of age (16). Also, peroxiredoxin 6 knockouts fed atherogenic diets. Strains the major atherosclerosis parameter may rest solely or were either 129 or C57BL/6 or a mixed strain, 129:BL/6. largely on the size of the lesions, often with little attention 129 animals were equally resistant whether or not the per- Getz Immune function in atherogenesis 7 oxiredoxin function was present. Similarly, the BL/6 networks, leading some investigators to adopt system-wide strain was equally sensitive with this gene functioning or approaches (62). In spontaneous atherosclerosis that is so not. A difference between knockout and control mice was prevalent in the human population, the modulation of seen with the mixed strain. The caveat is that all lesions gene function is probably much more subtle and com- were very early and were quite small (59). plex. The challenge for future studies of the role of the Hypercholesterolemia is a requisite for the develop- immune system in atherosclerosis is to model this com- ment of atherosclerosis in the mouse. The effects of im- plexity. This will require the selective and layered reconsti- mune modulators could operate on the level of hypercho- tution of the innate and adaptive immune systems, the lesterolemia or upon the responding blood vessel wall or manipulation of more than one cell type or more than perhaps at both levels. There are clearly some immune one cytokine or metabolite in particular models, and modulators that affect atherosclerosis without inﬂuencing more subtle modiﬁcation of gene function in particular the level of plasma lipoproteins. On the other hand, some cell components of the atherosclerotic plaque. immune modulators (e.g., IFN- signaling) do inﬂuence lipoprotein metabolism (60). The role of cytokines on lipo- The author is grateful to Irena Dopter for her help in the prepara- protein metabolism has mostly focused on the response to tion of the manuscript. The author thanks Catherine Reardon, Paul the cytokines of the acute phase response to infection VanderLaan, and Joseph Witztum for their critical reading of drafts (i.e., TNF-, IL-1, and IL-6) (61). However, global deﬁciency of the manuscript. The work of the author has been supported by of the adaptive immune system generally results in a re- National Institutes of Health Grants HL-56827 and HL-68661. duction in plasma cholesterol and triglyceride, especially in the VLDL fraction in both LDL receptor-deﬁcient and apoE-deﬁcient mice (53, 58). It has been reported that in the face of marked hypercholesterolemia in the apoE-deﬁ- REFERENCES cient mouse, global immunodeﬁciency has no effect on 1. Witztum, J. L. 2004. Thematic reviews on the pathogenesis of ath- atherosclerosis (57). We have recently shown that when erosclerosis. J. Lipid Res. 45: 991–992. apoE-deﬁcient mice backcrossed to BL/6 mice for 10 gen- 2. Glass, C. K., and J. L. Witztum. 2001. Atherosclerosis. 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J. Lipid Res., 45

Publisher: American Society for Biochemistry and Molecular Biology
Copyright: Copyright © 2005 Elsevier Inc.
ISSN: 0022-2275
eISSN: 1539-7262
DOI: 10.1194/jlr.r400013-jlr200
Publisher site: See Article on Publisher Site

Abstract

thematic review Thematic review series: The Immune System and Atherogenesis Immune function in atherogenesis Godfrey S. Getz Department of Pathology, Biochemistry, and Molecular Biology, University of Chicago, Chicago, IL Abstract In this overview to a new thematic series on the nisms. I will then update the information based upon immune system and atherogenesis, I provide a very brief studies published in the last 2–3 years. This will provide summary of current conceptions of atherogenesis, of the in- the backdrop for an introduction to this Thematic Series. nate and adaptive immune systems, and of the participation The overview will conclude with a set of additional com- of the latter in atherogenesis, with particular emphasis on ments that might be helpful in the consideration of im- studies of the involvement of the immune system in athero- mune system participation in the modulation of athero- sclerosis reported in the last 2 years. This is followed by a sclerosis. short outline of the eight reviews that will make up this the- matic series. The overview is concluded with some cave- ats that should be considered in the analysis of atheroscle- rosis in experimental animals.—Getz, G. S. The immune ATHEROSCLEROSIS AS CHRONIC INFLAMMATION system in atherogenesis. J. Lipid Res. 2005. 46: 1–10. It is now widely recognized that atherosclerosis is a spe- Supplementary key words innate immunity • adaptive immunity • cyto- ciﬁc example of a chronic inﬂammatory response mainly kines to dyslipidemia and other risk factors. This notion was ar- ticulated in an excellent article by Russell Ross (5). In keeping with this formulation, the atherosclerotic plaque This issue inaugurates a new Thematic Series that high- has as its major components macrophages, cells of the lights the role of immune function in atherosclerosis. To adaptive immune system, smooth muscle cells, and matrix quote from an earlier editorial inaugurating another The- components. As with most chronic inﬂammatory reac- matic Series: “the complexities of lipid and lipoprotein tions, the cells of the immune system have the potential to metabolism, and the differing responses of vascular wall signiﬁcantly inﬂuence the outcome of the inﬂammation. cells (including immune cells) to the interplay of lipopro- The atherosclerotic plaque is notable for its focal nature, teins and to the vast array of circulating cellular and blood being mostly encountered in regions of the macrovascula- elements, are enormous” (1). This viewpoint can be ap- ture subject to disturbed ﬂow hemodynamics. plied also to the interaction of the components of the im- In both human and experimental atherosclerosis, hy- mune system with lipid and lipoprotein metabolism in the percholesterolemia is the major exciting factor for the de- context of the evolution of the atherosclerotic plaque. velopment of vascular lesions. The increased cholesterol is A modern approach to the molecular pathogenesis of carried either by LDL or VLDL remnants. It is now atherosclerosis has been well reviewed (2). The role of in- thought that increased plasma levels of LDL result in en- nate and adaptive immunity in its pathogenesis has been hanced oxidation or perhaps other modiﬁcations of LDL comprehensively dealt with in two recent reviews (3, 4). within the vascular wall, representing a major initiating Readers are encouraged to consult each of these reviews agent for the formation of the atherosclerotic response. alongside of this overview. Lipoproteins retained in the vessel wall by matrix compo- Because the following series deals in depth with impor- tant aspects of immune function in relation to atheroscle- rosis, in this overview I will brieﬂy summarize the state of the subject, mostly as reﬂected in these aforementioned Abbreviations: apoE, apolipoprotein E; CD40L, CD40 ligand; CRP, three reviews. Here, the focus will be on the lesion out- C-reactive protein; dn, dominant negative; IL, interleukin; MHC, ma- come, without dealing with the detailed cellular mecha- jor histocompatibility complex; NF-B, nuclear factor B; NK, natural killer; NK-T, natural killer T; OxLDL, oxidized low density lipoprotein; RAG, recombination-activating gene; SAA, serum amyloid A; TCR, T-cell receptor; TGF, transforming growth factor; Th cell, T-helper cell; TNF, Manuscript received 2 November 2004. tumor necrosis factor. To whom correspondence should be addressed. Published, JLR Papers in Press, November 16, 2004. DOI 10.1194/jlr.R400013-JLR200 e-mail: [email protected] Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 46, 2005 1 This is an Open Access article under the CC BY license. nents, the most prominent of which are the proteogly- BRIEF SUMMARY OF THE IMMUNE SYSTEM cans, are probably especially susceptible to oxidation. Oxi- dation of retained lipoproteins may be a function of the The immune system has been recognized as an impor- production of reactive oxygen species generated by the tant component of atherosclerotic inﬂammation. The im- mune system can be thought of as two subsystems, the in- cells of inﬂammatory inﬁltrates or by enzymes such as li- nate immune system and the adaptive immune system. poxygenases produced by inﬁltrating macrophages. Mac- rophages import oxidized LDL (OxLDL) into the endoso- The innate immune system is critical to the initial inﬂam- mal system via a variety of scavenger-type receptors. The matory response. Several cellular and mediator responses are involved. The acute cellular response in the context of cholesterol so imported ultimately ends up in the cyto- atherosclerosis is centered on the monocyte-macrophage, plasm, where it is esteriﬁed, generating cholesteryl ester droplets and forming foam cells that are the hallmark of whose participation has been summarized above. Other early and growing atherosclerotic plaques. The accumula- cells may also play some role. This includes natural killer (NK) cells, dendritic cells, mast cells, and B1 cells. NK tion of such foam cells constitutes the bulk of the early cells, as the name implies, are able to kill tumor cells, vi- vascular lesion, designated by some as a fatty xanthoma (6). Oxidized phospholipid moieties of oxidized lipopro- rally infected cells, or antibody-coated cells. But they also teins signal to many of the cells in the evolving plaque, es- secrete cytokines, the most prominent of which is IFN-. NK cells when activated are particularly efﬁcient produc- pecially to the endothelium overlying the accumulating ers of IFN-, which activates macrophages (8). NK cell ac- OxLDL and to foam cells. Among other responses, this sig- naling increases the expression of adhesion molecules that tivity is inﬂuenced by other cytokines, such as IL-2, IL-15, facilitate the homing of monocytes and lymphocytes to and IL-12. Dendritic cells play a key role in antigen pre- sentation, expressing high levels of scavenger receptors this localized activated endothelium. The foam cells and and class II major histocompatibility complexes (MHCs), activated endothelium may also produce proinﬂamma- tory cytokines such as interleukin-1 (IL-1), IL-6, IFN-, which present antigens to cells of the adaptive immune and tumor necrosis factor- (TNF-) (7), which promote system. They also express costimulatory molecules, B7-1 and B7-2. Mast cells on activation release histamine, leuko- the further development of the inﬂammatory response. trienes, platelet-activating factor, proteases, and cytokines. Also, the elaboration of chemotactic factors such as MCP-1 attracts the further inﬂux of monocytes. The macrophage In a sense, all of the cells included in the initial atheroscle- foam cell is a very versatile multifunctional cell, capable of rotic response can be regarded as part of the innate im- mune response, because endothelial cells and smooth elaborating reactive oxygen species, prostaglandins, nitric muscle cells can be induced, for example by IFN-, to ex- oxide, and growth factors. Foam cell homeostasis is the re- sult of new recruitment and lipid loading on the one hand press class I and class II MHC proteins. The MHCs on and efﬂux of lipid on the other. The latter is promoted by these cells are capable of presenting antigens, although not nearly with the efﬁciency of the more traditional anti- apolipoprotein E (apoE), apoA-I, HDL, and the ATP bind- gen-presenting cells, macrophages, and dendritic cells. B1 ing cassette proteins ABCA1, ABCG1, and ABCG4. The progression of the lesion from the fatty xanthoma cells bridge the innate and adaptive immune systems. They to a more complex lesion is characterized by the migra- are responsible for the production of IgM antibodies, many of which react with oxidized phospholipids. These tion of smooth muscle cells from the media into the sub- antibodies have been shown to block the uptake of Ox- endothelial intima and their subsequent proliferation. This is mediated, in part, by the growth factors secreted LDL by macrophage scavenger receptors. The activation from macrophage foam cells. These smooth muscle cells of the inﬂammatory response induces the synthesis and release of IL-1, TNF-, and IL-6, which are responsible for may themselves become foam cells, but more importantly inducing in the liver the transcription of the acute-phase they are responsible for the synthesis of matrix proteins and proteoglycans. The foam cells may ultimately die ei- plasma proteins, including C-reactive protein (CRP), se- ther by necrosis or apoptosis, liberating their contained rum amyloid A (SAA), ﬁbrinogen, and ferritin, as well as proteins of the complement system. An outline of the in- lipid and producing a necrotic core with extracellular nate immune system is shown in Fig. 1. lipid. The death of foam cells is probably related to the dysregulation of intracellular lipid metabolism and the The adaptive immune system (Fig. 2) reacts to endoge- formation of cytotoxic oxidized sterols and other lipids. nous neoantigens (e.g., apoptotic cells or OxLDL) or ex- ogenous antigens, resulting in the activation of T-cells and Late atherosclerotic plaques may also undergo cartilagi- B-cells. Some of these neoantigens are also targets of the nous dysplasia with calcium deposition. The increase in the size of the evolving atherosclerotic plaque arises from innate immune system. The adaptive immune system may the continued recruitment of monocytes and lymphocytes, inﬂuence atherosclerosis in one of three ways: 1) by cell- cell interaction (e.g., between antigen-presenting cells, the continued migration and proliferation of smooth macrophages, B-cells, or dendritic cells) and T-cells; 2) by muscle cells, the evolution of a necrotic core, and matrix protein synthesis. Activation of the macrophages in the le- the secretion of a variety of cytokines from activated T-cells, sions, particularly on the lesion shoulders, may lead to the which mediate an activation of macrophages and other cells of the atherosclerotic plaque; or 3) by the produc- release of proteases, with disruption of the plaque sur face tion of antibodies by B-cells in a T-cell-dependent or -inde- giving rise to the unstable plaque lesion becoming the ni- dus for thrombosis and consequent clinical complications. pendent manner. Some of these antibodies have the ability 2 Journal of Lipid Research Volume 46, 2005 Fig. 2. Adaptive immunity. This network is activated by exposure to either neoantigens such as OxLDL and heat shock proteins (hsps) or exogenous antigens such as chlamydial antigens. These antigens are processed and presented by antigen-presenting cells (dendritic cells, macrophages, or B-cells) in the context of major histocompatibility complex (MHC) class I or II or CD1 for den- dritic cells and macrophages and the B-cell receptor in the case of Fig. 1. Innate immunity. The liver produces the major actor in B-cells. The antigen-presenting cells present antigen to CD4 T-cells atherogenesis in the form of VLDL, which in transit through the bearing cognate T-cell receptors, resulting in activation of the T-cells plasma is converted to LDL. Some of the LDL enters the subendo- but only in the presence of the second signal produced by costimu- thelial space, where it may be oxidized, forming oxidized LDL (Ox- latory molecules (e.g., B7-1, B7-2) interacting with CD28. B-cells ac- LDL). The liver in a proinﬂammatory state [i.e., increased cyto- tivated by antigens may also interact with T-cells via the CD40-CD40 kines interleukin-1 (IL-1), IL-6, and tumor necrosis factor- (TNF-)] ligand (CD40L) pair of costimulatory molecules predominantly in- also produces many acute phase proteins, some of which are listed. volved in this interaction but also in other cell-cell interactions. The Their direct participation in the process of atherogenesis is not yet activated and selected T-cells may differentiate into T-helper cell 1 clear. Components of the OxLDL elicit the activation of endothe- (Th1) or Th2 subsets, producing predominantly IFN- and IL-4, re- lial cells, resulting in the upregulation of adhesion molecules, spectively. IFN- may positively feed back on the activity of the anti- which facilitate the entry of blood monocytes into the subendothe- gen-presenting cells, whereas IL-4 facilitates the differentiation of lial space. Here, monocytes may be converted to macrophages ex- B-cells into antibody-producing cells. The third subset of CD4 pressing cell surface scavenger receptors, which mediate the im- cells are the natural killer T (NK-T) cells, which most often see lipid port of OxLDL, which contains the cholesterol that is stored in the antigen in the setting of CD1 on dendritic cells or macrophages. cell as cholesteryl ester (CE), forming the droplets characteristic of NK-T cells, unlike most of the other CD4 T-cells, may produce the foam cell of the evolving lesion. The monocyte macrophage is a both IFN- and IL-4. The B-cells produce antibodies of the IgM or multipotential cell, and some of its secreted products are listed. IgG types that interact with the antigens of modiﬁed LDL or other These products inﬂuence the evolution of the plaque, the autoacti- relevant antigens. This ﬁgure is modiﬁed by permission from the vation of the inﬂammatory reaction, and the migration of smooth ﬁgure in Hansson et al. (4). muscle cells to the subendothelial space, where they contribute to lesion evolution. Natural killer (NK) cells may also enter the suben- dothelial space and produce many cytokines or chemokines, but on their surface in the context of MHC class I or II mole- mostly IFN-, which among other actions activates the monocyte cules. Such antigenic epitopes interact with cognate T-cell macrophage. The B1 cell, which is not present in the lesion, receptors (TCRs) on the surface of T-cells, which respond bridges the innate and adaptive immune systems and may produce either by anergy or activation. The decision between these IgM antibodies that inhibit the uptake of OxLDL into the macro- phage, slowing its conversion to a foam cell. CRP, C-reactive pro- responses is largely determined by the availability of co- tein; MCP1, monocyte chemotactic protein 1; PDGF, platelet de- stimulatory molecules (e.g., B7-1 or B7-2) on antigen-pre- rived growth factors; SAA, serum amyloid A; SMC, smooth muscle senting cells that interact with CD28 on T-cells. The pool cells; TGF, transforming growth factor. of individual TCRs is enormous, arising during T-cell de- velopment as a result of gene rearrangements involving to block the import of modiﬁed lipoproteins via macro- many genes, including the obligatory recombination-acti- vating genes (RAG 1 and 2). The bulk of the T-cells ex- phage scavenger receptors. press the TCR consisting of a heterodimer of and chains. Antigenic molecules are processed within the endoso- A small proportion of T-cells express a TCR consisting of mal system of antigen-presenting cells and are presented Getz Immune function in atherogenesis 3 and subunits. The latter T-cells recognize antigens with- differences both in the distribution of lesions (e.g., aortic out the necessity that they be presented on MHC mole- root dominance in the mouse) and in the quality of the le- cules. Although these cells are capable of generating a sions. large variety of antigen receptors, most of them recognize Several lines of evidence have been adduced to impli- a limited number of antigens (9). Some of these cells re- cate the immune system in the process of atherosclerosis. spond to heat shock proteins (10). First, the presence of immune cells and immune cell T-cells may be divided into CD4 and CD8 subclasses. products in the human and/or experimental atheroscle- The majority of T-cells in atherosclerotic plaques are CD4 rotic lesion is taken to indicate their likely participation in cells, although smaller numbers of CD8 cells have been the lesion biology. Millonig, Malcom, and Wick (12) have detected. CD4 cells recognize antigen loaded on MHC described a “vascular associated lymphoid tissue” in vascu- class II molecules of the antigen-presenting cell, whereas lar regions susceptible to atherosclerosis. Macrophages and CD8 cells recognize antigens presented in the context T-cells are detectable in this tissue even before the plaque of MHC class I molecules. Among the CD4 cells are sev- develops. Among the immune cells and molecules de- eral subgroups, three of which have been investigated in tected in human atherosclerotic plaques are macrophages, murine atherosclerosis. These subgroups are distinguished dendritic cells (13), CD4 T-cells, CD8 T-cells, MHC by the complement of cytokines they produce. Th1 cells class II, CD40, and CD40L, the cytokines IL-1, IL-2, IFN-, mainly secrete proinﬂammatory cytokines such as IFN-, IL-7, IL-10, IL-12, IL-18, TNF-, transforming growth fac- which activates macrophages and facilitates the produc- tor- (TGF), as well as immunoglobulin (4, 12). The cy- tion of antibodies of the IgG2a class by B-cells. T-helper 1 tokines of Th2 cells are present at much lower levels (7). (Th1) cells do not secrete IL-4 or IL-5. Th2 cells, on the The presence of both proinﬂammatory and anti-inﬂam- other hand, secrete IL-4 and IL-5 but not IFN-. These matory cytokines speaks to the possibility of the coexistence cells provide help for the synthesis of other antibody of proatherogenic and antiatherogenic inﬂuences in le- classes. The Th2 cytokines may be anti-inﬂammatory. There sions. B-cells are relatively rare among the cells of the hu- is cross-regulation among these two subsets of T-cells, so man atherosclerotic plaque, although they may be found that each tends to inhibit the other. IFN- inhibits Th2 in the neighboring adventitia. cells and IL-4 inhibits Th1 cell cytokine secretion. Also, Second, more compelling evidence for the role of the IL-10 inhibits the Th1 pathway, whereas IL-12 reduces the immune system in atherogenesis derives from speciﬁc Th2 responses (4). A third special subset of T-cells are the gene deletion or overexpression in mice. The knockout of natural killer T cells (NK-T cells), which bear some of scavenger receptors (SR-A, CD36), mediators of monocyte the same markers as NK cells, but unlike the latter they ex- chemotaxis (MCP-1, CCR ), IFN- or its receptor, costimu- press rearranged cell surface TCRs of limited diversity. latory molecules, CD40L, and the RAG genes, resulting in They mainly recognize lipid antigen in the context of the global immunodeﬁciency, all lead to a reduction in ath- MHC-like compound CD1. There are other T-cell subsets erosclerosis in mouse models (3, 4). On the other hand, that have been less studied in atherosclerosis (e.g., T-regu- the knockout of the Th1 inhibitory cytokine, IL-10, results latory cells, Th3 cells, etc.). in an increase in lesions. The pattern of cell and cytokine B-cells are the other major group of circulating lympho- involvement suggests a Th1 dominance in atherosclerotic cytes. They recognize antigen via the B-cell antigen recep- lesions. This dominance has been reported to reverse in tor, in which cell surface IgM plays a central role. Like T-cells, the face of marked hypercholesterolemia, at least in the B-cells, through these receptors, express unique speciﬁc- apoE-deﬁcient mouse (14). The Th2 cytokine IL-4 was ity derived from the rearrangement of immunoglobulin thought to afford protection, but its inﬂuence may be genes, a process that is also RAG dependent. Mature B-cells, more complex, because IL-4 deﬁciency in the background designated as plasma cells, secrete speciﬁc antibodies. of either apoE deﬁciency or LDL receptor deﬁciency leads The production of antibodies to protein antigen requires to a reduction in lesion size (15, 16). This argues that cyto- T-cell help. The interaction between T-cells and B-cells is fa- kine effects might not be simply explained by resorting to cilitated by CD40 ligand (CD40L) expressed on T-cells the Th1/Th2 paradigm. Non-T-cell-dependent effects of and CD40 on B-cells. IL-4 may be at work (16). Recently, IL-5 has been reported to play a protective role (17). Cytokine effects on athero- genesis indeed seem to be quite complex. The knockout of immunoglobin results in a B-cell deﬁciency. Trans- IMMUNE MODULATION OF ATHEROSCLEROSIS plantation of bone marrow cells from B-cell-deﬁcient mice This topic is studied in both human atherosclerosis and into LDL-deﬁcient mice results in an increase in athero- experimental models of atherosclerosis, with the mouse sclerosis (18). This indicates that B-cells may have a pro- now holding pride of place because of the capacity to ma- tective effect on atherosclerosis, despite their relatively nipulate almost at will its genetic program. Indeed, differ- rare appearance within the plaque. This suggests that ent strains of mice exhibit quite different susceptibilities their effects may be mediated by the antibodies they se- to atherosclerosis (11), indicating the importance of ge- crete, or perhaps by some other immunoregulatory role. netic modiﬁers in the evolution of the atherosclerotic le- A third basis for implicating the immune system in sion. The murine lesion bears many similarities to the hu- atherogenesis is provided by the direct transfer of immu- man lesion, but it is worth noting that there are some nological mediators. IFN-, IL-12, or IL-18 injection all in- 4 Journal of Lipid Research Volume 46, 2005 crease atherosclerosis (3). The administration of antibod- tor and lysophosphatidic acid, which are likely to be en- ies to CD40L reduces lesion formation in LDL receptor- riched in progressing lesions. deﬁcient mice, whereas the use of antibodies to TGF in the apoE-deﬁcient mouse increases atherosclerosis, em- phasizing the atheroprotective inﬂuence of this cytokine. ADAPTIVE IMMUNITY The fourth type of evidence directing attention to the role of the immune system involves immune cell transfer With respect to the adaptive immune system, NK-T cells or vaccination. When CD4 cells from apoE-deﬁcient mice have entered the atherosclerosis arena. As they recognize in which the Th1 cell subtype is dominant are transferred lipid antigen in the context of CD1, their involvement is to immunodeﬁcient apoE-deﬁcient mice, an increase in worthy of consideration. Their activation increases athero- atherosclerosis is noted (19). On the other hand, the sclerosis in the apoE-deﬁcient model (28). It has recently transfer of B-cells from apoE-deﬁcient mice with or with- been shown that regulatory T-cell subtype 1 upon transfer out T-cells reduces atherosclerosis (20). The two major an- to apoE-deﬁcient mice reduces atherosclerosis. This is as- tigens to which autoantibodies are detected are OxLDL sociated with a reduction in the IFN--to-IL-10 ratio (29). and heat shock proteins. Vaccination with the former de- The role of costimulatory molecules has been empha- creases lesion formation, whereas in the case of the latter, sized recently (30). It has been known for some time that atherosclerosis is increased (3). the CD40-CD40L interaction is implicated in atheroscle- In the last 18–24 months (i.e., since the publication of rosis (31). These molecules are members of the TNF su- the two reviews brieﬂy summarized above), many addi- perfamily. An alternative name for CD40 is TNF receptor tional studies have been published that bear on the topic superfamily 5 (TNFRSF 5), and the CD40 is designated of this overview. TNFSF 5 (31, 32). Although the expression of this pair was thought to be restricted to B-cells, dendritic cells, and activated T-cells, it is now clear that they are more widely expressed in the cells present in atherosclerotic plaques. INNATE IMMUNITY Interdiction of their interaction results in a reduction in lesion development, while also modifying the composition In relation to the innate immunity network, the poten- of the lesion toward a less inﬂammatory and more ﬁbro- tial proatherogenic role of NK cells has received renewed genic lesion phenotype (31). Another pair of costimula- attention (21, 22). Dendritic cells seem to be concentrated tory molecules that belong to the TNF superfamily is in the rupture-prone areas of vulnerable human carotid LIGHT (TNFSF 14) (32) and its receptor, either HVEM artery plaques (23). There has of course been continued (TNFRSF 14) expressed on lymphocytes and NK cells or study of CRP and its role as a marker of or a participant in lymphotoxin expressed on stromal cells and monocytes atherosclerosis. The involvement of the Toll-like receptors (33). These molecules have been noted in human athero- in signaling and the initiation of atherosclerosis has also sclerotic plaques clustered in macrophage-rich regions, been studied recently. Among the hepatic products that and their properties suggest that their interaction is proin- participate in the anti-inﬂammatory response is the com- ﬂammatory (34, 35). The other costimulatory pair is B7-1 plement system, which can be activated by CRP (24). The (CD80) and B7-2 (CD86). They are members of the im- complement peptides C3a and C5a may be chemotactic munoglobulin superfamily, are expressed in antigen-pre- for monocytes. The lack of complement component 5 in senting cells, and bind to CD28 on resting T-cells. B7-1 and apoE-deﬁcient mice apparently has little impact on ath- B7-2 overlap in function. When their coupled absence is erosclerosis. On the other hand, C3 deﬁciency studied in combined with LDL receptor deﬁciency, atherosclerosis is the model that is lacking both apoE and the LDL receptor reduced and the lesions have fewer T-cells, smooth muscle resulted in an increase in aortic lesions, although cross- cells, and less collagen (36). Thus, like the other pairs of sectional analyses of the aortic root showed no difference costimulatory molecules, they are proinﬂammatory. in the size of the lesions (25). The C3-deﬁcient mice had increased triglyceride and LDL cholesterol levels. Aortic atherosclerosis in C3-deﬁcient mice crossed with the LDL receptor-deﬁcient model was also increased (26). CYTOKINES Most of the emphasis in atherogenesis has been on the recruitment of monocytes into the lesion-prone areas, As described above, cytokines play important roles in where they become macrophage foam cells. The fact that modulating atherosclerosis. Lymphotoxin also func- lesions regress, leaving fewer macrophages, implies that tions as a proinﬂammatory cytokine in murine atheroscle- these cells must have the capacity to migrate out of the le- rosis (37). Either the absence of IL-1 or a reduced gene sion. In an elegant transplant model, Llodra and col- dosage of IL-1 receptor antagonist in the apoE-deﬁcient leagues (27) have demonstrated the outward migration of background suggests an inﬂuence of IL-1 in promoting macrophages and dendritic cells from the lesion-ﬁlled atherogenic cell signaling (38, 39). The larger lesions of aortic arch of an apoE-deﬁcient mouse when the arch was the IL-1 receptor antagonist-deﬁcient mice are enriched transplanted into a wild-type mouse. The migration ap- in macrophages relative to smooth muscle cells. pears to be limited by lipids, such as platelet-activating fac- Information on the role of the proinﬂammatory cyto- Getz Immune function in atherogenesis 5 kine IFN- produced mainly by Th1 and NK cells has been are signiﬁcantly distinct, so that further investigation is re- extended in several experiments. The knockout of IFN- quired to resolve the discrepancy. in the LDL receptor-deﬁcient background substantially re- duced lesion size in several regions of the aorta, with a rel- ative loss of macrophages and smooth muscle cells in the THIS SERIES early lesions (40). IFN-, which has previously been re- ported to downregulate the SRA and CD36 scavenger recep- There will be eight substantial reviews in this series, all tors, is thought to be important for the uptake of modiﬁed of which deal with currently active topics. Four of these will be devoted largely to the innate immune system, and lipoproteins and foam cell formation. IFN- has now been the others will deal with the bridge between innate immu- shown to upregulate another scavenger receptor, SR-PSOX, which recognizes phosphatidylserine and OxLDL. SR-PSOX nity and the adaptive immune response. Because macro- is identical to the transmembrane protein CXCL16, a che- phages are the hallmark of the atherosclerotic lesion, they will be heavily represented in at least half of the reviews. mokine receptor involved in T-cell migration. SR-PSOX The ﬁrst of these will be devoted to the increasing variety and its receptor are present in atherosclerotic lesions (41). The dominance of Th1 and their secreted products of scavenger receptors expressed on the macrophage and within the plaque is balanced by counterinﬂammatory in- dendritic cell surfaces. David Greaves and Siamon Gor- don will discuss how these receptors might be involved in ﬂuences, mediated in part by IL-10, expressed in macro- atherogenesis, but they will also address other aspects of phages and Th2 lymphocytes in the plaque. When LDL receptor-deﬁcient mice are transplanted with bone mar- the biology of these receptors. This review will be followed row overexpressing IL-10 in T-cells, atherosclerosis is re- by an overview of the currently very active ﬁeld of the role of acute phase proteins, such as CRP, SAA, and other duced (42). In contrast, the transplantation of IL-10-deﬁ- members of this family. This will be reviewed by Alan cient bone marrow into LDL receptor-deﬁcient mice led to a marked increase in lesion development at several Chait, Jack Oram, and Jay Heinecke. One of the major is- sites, and these lesions were rich in macrophages and lym- sues to be addressed relates to the possibility that these proteins are directly involved in atherosclerosis, rather phocytes (43). Nuclear factor B (NF-B) mediates many than “simply” serving as markers of the inﬂammatory proinﬂammatory effects. The recent observation that se- lective attenuation of NF-B signaling in macrophages re- state. Much work has been done on the possible proat- sults in an increase in atherosclerosis in the LDL receptor- herogenic inﬂuence of microorganisms such as Chlamydia. The recognition of the cell surface molecules of these or- deﬁcient background is somewhat surprising (44). This ganisms is via the so-called Toll-like receptors, which are could be attributed to the substantial reduction in IL-10 production. A most interesting recent ﬁnding hypothe- expressed on such cells as macrophages, neutrophils, NK sizes that IL-5 inﬂuences the stimulation of the produc- cells, dendritic cells, and endothelial cells. These recep- tors may signal to the transcriptional machinery of the cell tion of anti-oxidized phosphatidylcholine antibodies after to promote a proinﬂammatory state. There are at least 10 immunization with malondialdehyde LDL (17). The im- munization caused a preferential expansion of cognate such receptors with differing speciﬁcity and cell distribu- Th2 cells that secrete IL-5, which then stimulates B1 cells. tion. Recent papers have implicated some of these recep- tors in atherogenesis (50, 51). This subject will be re- This provides a link between natural and adaptive immu- viewed by Linda Curtiss. nity and will be fully discussed in the thematic review by Binder, Witztum, and colleagues on natural antibodies. I will then comment on the bridge between innate and The atheroprotective cytokine TGF has also received adaptive immunity in an extended editorial. This will be followed by a review of the natural antibodies recognizing considerable attention. It functions as an anti-inﬂamma- modiﬁed lipoproteins and apoptotic cells as well as mole- tory cytokine, limiting the recruitment of leukocytes and promoting the synthesis of collagen and extracellular ma- cules that mimic these antigens. This is an exciting ﬁeld trix (45, 46). TGF-deﬁcient mice die early, so alternative with continuing surprises pointing in new directions of substantial potential clinical signiﬁcance. The recent ob- strategies are used to attenuate its function. Most have used servations in this area will be reviewed by Peter Shaw, Chris- either a soluble TGF receptor that inhibits signaling (47) or a dominant negative (dn) mutant receptor driven by a toph Binder, and Joseph Witztum and colleagues, who have T-cell-speciﬁc promoter (CD2 or CD4) expressed as a trans- contributed greatly to this ﬁeld. As mentioned above, a number of lymphocyte sub- gene (48, 49). These studies noted some similarities and classes have come into sharp focus as inﬂuencing athero- some discrepancies. In the Robertson study (48), T-cell dn receptor-expressing mice were crossed with apoE-deﬁ- genesis. This includes B1 cells, NK cells, and NK-T cells. cient mice, whereas in the Gojova study (49), bone mar- These unusual suspects as well as dendritic cells and their contribution to atherogenesis will be reviewed by Cath- row was transplanted from dn TGF receptor-expressing erine Reardon and Paul VanderLaan. mice into LDL receptor-deﬁcient mice. Both groups of in- vestigators noted lesions that exhibited increased T-cells, It is clear from the above overview that the atheroscle- macrophages, and reduced collagen, an inﬂammatory rotic plaque is a “soup” of cytokines, produced by many cell types within the inﬂammatory plaque and acting upon phenotype. The Robertson study noted increased lesion many of their neighbors. Knockout experiments and other size, whereas a modest reduction in aortic root lesions was noted in the Gojova study. These experimented models manipulation of expression levels of these molecules clearly 6 Journal of Lipid Research Volume 46, 2005 demonstrate their inﬂuence on the atherogenic process. to the lesion phenotype or detailed morphology. In model- We have asked Elaine Raines and Alan Daugherty to focus ing lesions of clinical relevance, the quality and composition our attention on the role of these cytokines on target cells of the lesion is probably of more importance. In accepting within the plaque. Elaine Raines will do this for endothe- the general view of the mechanisms of atherogenesis, one lial cells and smooth muscle cells. Alan Daugherty will in- should bear in mind the potential limitations in the evi- form us about the macrophage and leukocytes as targets. dence that supports this view. We will conclude the series by a return to the central Some interventions have modest effects on the size of role of the monocyte, which must be recruited into the the lesion but do inﬂuence the lesion phenotype. This is evolving lesion to fulﬁll its critical participation. Thus, Os- exempliﬁed in recent murine atherosclerosis studies on wald Quehenberger will review monocyte chemotaxis and IFN- deﬁciency in atherosclerosis in the LDL receptor- atherogenesis. deﬁcient mouse (40). Lesion phenotype is dramatically changed with modulation of IL-10 signaling and attenua- tion or alteration of TGF signaling (42, 43, 47, 49). We have previously drawn attention to the differential ADDITIONAL COMMENTS responses of various vascular regions to immune modula- In summary, the prevailing evidence suggests that ath- tion (52). We suggest that this is attributable to the way re- erosclerosis progression represents a chronic inﬂammatory gional differences in hemodynamic proﬁles prime the en- reaction involving the participation of the innate immune dothelial phenotype to respond to such modulations. An system and modulated by the adaptive immune system. In alternative explanation could be that differences in the the latter case, the proinﬂammatory pattern dominates as microenvironment in the subintimal space in which le- a result of Th1 cells secreting IFN-, a situation stimulated sions develop condition the atherosclerotic response. We by IL-12 and IL-18. However, it seems clear that develop- have seen this in comparing the response of the aortic ing atherosclerotic plaques represent a balance between root and the innominate artery to immune deﬁciency in proinﬂammatory and anti-inﬂammatory inﬂuences, with the LDL receptor-deﬁcient model (53). Other examples the former being dominant during early plaque evolu- of the differential response of aortic regions to immune tion. That there are anti-inﬂammatory inﬂuences at work modulators include IL-4 deﬁciency combined with LDL is indicated by the experimental manipulation of IL-4, IL-10, receptor deﬁciency, in which there was no impact on the and TGF as discussed above. Also, B-cells and their se- aortic root lesion size but substantially reduced lesion size creted antibodies recognizing relevant antigens may con- in the aortic arch and thoracic aorta (15). A second exam- tribute to some degree of atheroprotection. However, the ple involves immunization of LDL receptor-deﬁcient mice adaptive immune system is not required for the develop- with OxLDL, which reduced aortic root lesion size but ment of atherosclerosis. Quite substantial lesions develop had no inﬂuence on lesions in the remainder of the aorta in the absence of mature T- and B-cells in mouse models (54). The majority of studies of atherosclerosis in the in which the function of the RAG gene(s) is eliminated. mouse have examined lesions in the aortic root or in the Our current conception of experimental atherosclero- whole aorta by en face analysis. Given the hitherto re- sis derives predominantly from a limited examination of ported differences in response according to the vascular atherosclerosis either by the measurement of aortic root region examined, it seems that our understanding of the lesions, not a characteristic site for human atherosclerosis, interplay of the immune system on murine atherosclerosis or en face measurement of the extent of aortic lipid le- would be greatly enhanced by measuring the atheroscle- sions. Sometimes both methods are used. This examina- rosis response at more than one vascular site. A dramatic tion may be undertaken early in atherosclerosis, when the example of such a difference is shown by the surprising in- predominant lesion is a fatty streak (xanthoma), or later, crease in abdominal aortic atherosclerosis seen in female when more complex lesions are seen. It should not be a apoE-deﬁcient mice also lacking CD4 cells (55). surprise that inﬂuences on early lesions and more complex It is well known that mouse strains differ in their suscep- lesions may differ. In the early lesion, composed mostly of tibility to atherosclerosis, with the C57BL/6 strain being foam cells, the cellular composition is reasonably homoge- the most sensitive. Many of the earlier experiments used neous. On the other hand, as the lesion increases in com- mouse strains that were not fully backcrossed into this ge- plexity, the potential for cellular interactions may be very netic background. Often, strain 129 was originally used different. The microarchitecture of the lesion, with the for the generation of the knockout mice. This was the case stromal separation of clusters of cells of different func- for the knockout of the RAG genes. The initial work on tion, could inﬂuence the measured outcome of an inter- the apoE-deﬁcient strains lacking the RAG genes used an- vention. Seldom does a single investigator examine lesions imals of modestly mixed background (56–58). We have at two different times, and this can be misleading, because shown that the effect of immune deﬁciency on innomi- the selection of a particular time point as readout may nate artery atherosclerosis in LDL receptor-deﬁcient mice bias the results in a lesion that evolves over time. For exam- is quite sensitive to the genetic background (53). An inter- ple, in apoE/IL-12-deﬁcient mice, lesion area is reduced esting illustration of this complexity is shown in studies of at 30 weeks of age but not at 45 weeks of age (16). Also, peroxiredoxin 6 knockouts fed atherogenic diets. Strains the major atherosclerosis parameter may rest solely or were either 129 or C57BL/6 or a mixed strain, 129:BL/6. largely on the size of the lesions, often with little attention 129 animals were equally resistant whether or not the per- Getz Immune function in atherogenesis 7 oxiredoxin function was present. Similarly, the BL/6 networks, leading some investigators to adopt system-wide strain was equally sensitive with this gene functioning or approaches (62). In spontaneous atherosclerosis that is so not. A difference between knockout and control mice was prevalent in the human population, the modulation of seen with the mixed strain. The caveat is that all lesions gene function is probably much more subtle and com- were very early and were quite small (59). plex. The challenge for future studies of the role of the Hypercholesterolemia is a requisite for the develop- immune system in atherosclerosis is to model this com- ment of atherosclerosis in the mouse. The effects of im- plexity. This will require the selective and layered reconsti- mune modulators could operate on the level of hypercho- tution of the innate and adaptive immune systems, the lesterolemia or upon the responding blood vessel wall or manipulation of more than one cell type or more than perhaps at both levels. There are clearly some immune one cytokine or metabolite in particular models, and modulators that affect atherosclerosis without inﬂuencing more subtle modiﬁcation of gene function in particular the level of plasma lipoproteins. On the other hand, some cell components of the atherosclerotic plaque. immune modulators (e.g., IFN- signaling) do inﬂuence lipoprotein metabolism (60). The role of cytokines on lipo- The author is grateful to Irena Dopter for her help in the prepara- protein metabolism has mostly focused on the response to tion of the manuscript. The author thanks Catherine Reardon, Paul the cytokines of the acute phase response to infection VanderLaan, and Joseph Witztum for their critical reading of drafts (i.e., TNF-, IL-1, and IL-6) (61). However, global deﬁciency of the manuscript. The work of the author has been supported by of the adaptive immune system generally results in a re- National Institutes of Health Grants HL-56827 and HL-68661. duction in plasma cholesterol and triglyceride, especially in the VLDL fraction in both LDL receptor-deﬁcient and apoE-deﬁcient mice (53, 58). It has been reported that in the face of marked hypercholesterolemia in the apoE-deﬁ- REFERENCES cient mouse, global immunodeﬁciency has no effect on 1. Witztum, J. L. 2004. Thematic reviews on the pathogenesis of ath- atherosclerosis (57). We have recently shown that when erosclerosis. J. Lipid Res. 45: 991–992. apoE-deﬁcient mice backcrossed to BL/6 mice for 10 gen- 2. Glass, C. K., and J. L. Witztum. 2001. Atherosclerosis. 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Journal of Lipid Research – American Society for Biochemistry and Molecular Biology

Published: Jan 1, 2005

Keywords: innate immunity; adaptive immunity; cytokines

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Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

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Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis

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