Inflammation in atherosclerosis

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Archives of Cardiovascular Disease (2016) xxx, xxx—xxx

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REVIEW

Inflammation in atherosclerosis L’inflammation dans l’athérosclérose Soraya Taleb Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Centre, Université Paris-Descartes, 56, rue Leblanc, 75015 Paris, France Received 8 February 2016; received in revised form 8 April 2016; accepted 11 April 2016

KEYWORDS Atherosclerosis; Inflammation; Monocytes; Macrophages; Lymphocytes

Summary Atherosclerosis is an inflammatory disease within the arterial wall that is responsible for several important adverse vascular events, including coronary artery disease, myocardial infraction, stroke and peripheral artery disease. Both innate and adaptive immunity play important roles in the development of atherosclerosis. In particular, monocytes/macrophages, which are the surrogate cells of innate immunity, have important proatherogenic effects. In addition, adaptive immune responses effected by T cells play important roles in atherosclerosis. While the T-helper cell type 1 (Th1) response has a potent proatherogenic effect, the pathogenic roles of other T cell subsets, such as the Th2 and Th17 pathways, remain controversial. However, the antiatherosclerotic protective roles of regulatory T cells and some Th2-related cytokines, such as interleukin-5, have been clearly established. In light of numerous data in animal models showing the importance of inflammatory cells in atherosclerosis and its complications, treatment of cardiovascular diseases with anti-inflammatory drugs may be an attractive strategy. However, future randomized placebo-controlled trials are required to test this possibility, to evaluate the proper effect of anti-inflammatory drugs as cardiovascular therapeutic agents without confounding effects. © 2016 Elsevier Masson SAS. All rights reserved.

Abbreviations: BAFF, B cell activating factor; FOXP3, forkhead box/winged helix transcription factor; Ig, immunoglobulin; IL, interleukin; iTreg, induced regulatory T cell; MMP, matrix metalloproteinase; OSE, oxidation specific epitopes; oxLDL, oxidized low-density lipoprotein; ROR, retinoid-related orphan receptor; TGF-␤, transforming growth factor-␤; Th, T-helper; Treg, regulatory T cell. E-mail address: [email protected] http://dx.doi.org/10.1016/j.acvd.2016.04.002 1875-2136/© 2016 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Taleb S. Inflammation in atherosclerosis. Arch Cardiovasc Dis (2016), http://dx.doi.org/10.1016/j.acvd.2016.04.002

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MOTS CLÉS Athérosclérose ; Inflammation ; Monocytes ; Macrophages ; Lymphocytes

Résumé L’athérosclérose est une maladie inflammatoire au sein de la paroi artérielle, qui est responsable de plusieurs complications importantes, comme l’infarctus du myocarde, l’accident vasculaire cérébral. À la fois, l’immunité innée et adaptative jouent un rôle important dans le développement de l’athérosclérose. En particulier, les monocytes/macrophages qui sont les cellules principales de l’immunité innée ont été montrées comme ayant un effet proathérogène. Également, les réponses immunitaires adaptatives représentées par les cellules T jouent un rôle important dans l’athérosclérose. Tandis que la réponse Th1 présente un effet pro-athérogène incontestable, le rôle pathogène d’autres sous-ensembles de lymphocytes T tels que Th2 et Th17 reste controversé. Cependant, le rôle protecteur des cellules T régulatrices contre l’athérosclérose et de certaines cytokines Th2, telles que l’IL-5 a été clairement établi. À la lumière de nombreuses données dans des modèles animaux montrant l’importance de cellules inflammatoires dans l’athérosclérose et de ses complications, le traitement des maladies cardiovasculaires avec des agents anti-inflammatoires peut représenter une stratégie intéressante. Cependant, des études futures sont nécessaires pour tester cette possibilité dans des essais contrôlés et randomisés pour évaluer les effets anti-inflammatoires propres de ces médicaments sans les effets cardiovasculaires confondants. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.

Background Atherosclerosis is responsible for several important adverse vascular events, including coronary artery disease, stroke and peripheral artery disease, which account for most cardiovascular morbidity and mortality. The prevalence of atherosclerosis is increasing worldwide, as a result of the adoption of the Western lifestyle, and is likely to reach epidemic proportions in the coming decades [1]. Nowadays, it is well recognized that atherosclerosis is a chronic inflammatory disease that occurs within the arterial wall, and is initiated mainly in response to endogenously modified structures, particularly oxidized lipoproteins (e.g. oxidized low-density lipoprotein [oxLDL]), which stimulate both the innate and adaptive immune responses [2,3]. The innate response starts with activation of endothelial cells in vessel walls and monocyte/macrophage activation; it is rapidly followed by an adaptive immune response to an array of potential antigens presented to effector T lymphocytes by antigen-presenting cells, such as dendritic cells. Both the innate and adaptive immune responses play important roles in the initiation and development of atherosclerosis, as shown using different animal models (Fig. 1). In particular, the reduction of macrophages in mice deficient for macrophage colony-stimulating factor protects against atherosclerosis [4]. Defective generation of T and B lymphocytes also significantly inhibits lesion development [5,6]. The roles of these different cell subtypes in the development of atherosclerosis are described below.

Role of monocytes/macrophages in atherosclerosis Monocytes play central roles in atherogenesis, and are rapidly attracted to sites of disturbed flow, characterized by low-grade inflammation [7]. Monocyte differentiation into macrophages is associated with upregulation of phagocytic activity, leading to lipid accumulation and the formation of

typical foam cells. These cells express an array of inflammatory factors, as well as matrix metalloproteinases (MMPs) that are responsible for matrix degradation, which may lead to plaque instability [8]. In human atherosclerotic plaques, an increase in MMP activity was detected in vulnerable areas [9]. At least two subsets of monocytes have been described in humans and mice. On the one hand, mouse Ly-6Chigh monocytes, which are similar to CD14high CD16− human blood monocytes (called ‘‘classical’’ monocytes) [10], express high levels of the chemokine receptor CCR2 and low levels of CX3CR1, and they rapidly infiltrate injured tissues and drive chronic inflammation [11]. On the other hand, ‘‘nonclassical’’ monocytes (Ly-6Clow in mice, CD14low CD16+ in humans) express high levels of CX3CR1 and low levels of CCR2, patrol the resting vasculature and may contribute to wound healing [12]. Circulating levels of classical monocytes, but not nonclassical monocytes, were independently associated with cardiovascular events (death, myocardial infarction and stroke) at follow-up in two relatively large cohorts of coronary patients [13] and in a randomly selected population [14]. Furthermore, CD14highCD16intermediate monocytes were shown to independently predict cardiovascular events in 951 subjects referred for elective coronary angiography [13]. Moreover, Reiner et al. [15] reported an independent association between circulating levels of soluble CD14 and incident cardiovascular events or all-cause mortality in European-American and black older adults. The infiltration of monocytes within plaques can give rise to foam cells, which may play an important role in plaque instability. However, cholesterol accumulation within macrophages does not necessary lead to inflammation. In fact, transcriptional analysis of peritoneal macrophages in wild-type versus Ldlr−/− mice fed either a chow or a high-fat high-cholesterol diet revealed an unexpected deactivation of the inflammatory response in the macrophage foam cells [16]. Furthermore, in humans, the use of an ACAT (acyl-coenzyme A cholesterol acyltransferase) inhibitor to block cholesterol accumulation within macrophages was

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Figure 1. Schematic representation of the differential roles and interactions between the various immune cell subsets in the context of atherosclerosis. Monocytes/macrophages, T-helper cells type 1 (Th1) and lymphocyte B2 cells (LB2) are the major proatherogenic mediators. On the other hand, regulatory T cells (Tregs) and some T-helper cells type 2 (Th2)-related cytokines (i.e. interleukin [IL]-5 and B1 cells) have been shown to have a protective role in atherosclerosis. The roles of other cell subtypes, such as Th17, and some Th2 cytokines (e.g. interleukin-4) remain controversial. IFN: interferon; Ig: immunoglobulin; LT: lymphocyte; TGF: transforming growth factor.

reported to be ineffective [17] or even to aggravate atherosclerosis [18]. Apoptotic cell clearance promotes resolution of inflammation through the production of anti-inflammatory mediators, such as interleukin (IL)-10 and transforming growth factor-␤ (TGF-␤). However, in atherosclerosis, defective clearance of apoptotic cells, called efferocytosis, leads to the formation of a necrotic core, which can aggravate inflammation and atherosclerosis (reviewed in [19]). Consistent with this, apoptosis was shown to be abundant in inflammatory regions [20], and localized in the site of human plaque rupture in sudden coronary death [21]. Thus, targeting efferocytosis might be an additional possibility in the treatment of atherosclerosis complications.

Role of T lymphocytes in atherosclerosis The first indications that adaptive immunity — particularly dendritic and T cells — plays a role in atherosclerosis were the presence of the major histocompatibility complex (MHC) class II cell surface receptor, HLA-DR, in human atherosclerotic plaques [22] and the existence of a large number of CD3+ T cells in atherosclerotic plaques in humans [23] and in mice [24]. The majority of T cells in mouse and human atherosclerotic plaques are CD4+ T-helper (Th) cells, expressing the ␣␤ T cell receptor. CD8+ T cells are also present in human atherosclerotic plaques [25], but are sparse in mouse lesions [26]. Like CD4+ cells, CD8+ T cells appear to promote atherogenesis in situations that activate this cell subset (reviewed in [26—28]).

T lymphocytes are among the earliest cells to be recruited into the atherosclerotic plaque [29]. In response to the local milieu of cytokines, CD4+ T lymphocytes differentiate into a Th1, Th2 or Th17 lineage. Besides producing specific cytokines of each pathway, Th1 and Th2 cells can promote humoral immune responses to specific antigens by stimulating the production of different immunoglobulin subtypes.

Th1 response in atherosclerosis All factors involved in the Th1 response, including expression of the Th1 transcriptional factor, T-bet, and production of interferon-␥, as well as factors known to induce its secretion, such as IL-12 and IL-18, have been shown to promote atherosclerosis (reviewed in [30]). In particular, a deficiency in T-bet, the interferon-␥ receptor or interferon-␥ significantly reduces lesion development, and defective interferon-␥ signalling enhances plaque collagen content [31—33]. In contrast, exogenous administration of interferon-␥ accelerates lesion development [33]. Interferon-␥ is known to activate monocytes/macrophages and dendritic cells, leading to perpetuation of the pathogenic Th1 response. In addition, interferon-␥ may inhibit vascular smooth muscle cell proliferation and reduce collagen production by these cells, while upregulating the expression of MMPs, thereby contributing to the thinning of the fibrous cap [2]. In humans, IL-18, which stimulates interferon-␥ production, was increased in the plasma of patients with coronary artery disease [34] and was a strong predictor of cardiovascular death in stable and unstable angina [35]. In addition, CD40—CD40L interactions, which

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promote Th1 development, are involved in atherosclerosis (reviewed in [36]). Human atherosclerotic lesions showed expression of immunoreactive CD40L on endothelial cells, smooth muscle cells and macrophages, while normal arterial tissues contained no CD40L, suggesting a potential effect of CD40—CD40L interactions in atherosclerosis [37]. Moreover, polymorphisms in the CD40 gene correlated with unstable coronary plaques or an increased risk of coronary plaque disruption in 699 patients [38]. Also, soluble CD40L in the circulation is highly correlated with cardiovascular risk in humans [39,40]. Collectively, these data provide convincing arguments to show that the Th1 pathway exhibits a potent proatherogenic effect.

Th2 response in atherosclerosis Th2 cells secrete IL-4, IL-5, IL-10 and IL-13, and also have the faculty to activate B cells to produce antibodies. The Th2 response was initially proposed to be atheroprotective, through Th1 response inhibition. However, the role of the Th2 pathway in the development of atherosclerosis remains controversial, depending on the stage and/or site of the lesion, the type of Th2-secreted factor and the experimental model. For example, the role of IL-4 in atherosclerosis is still under debate, but seems rather to have a proatherogenic effect. In Ldlr—/—mice, a deficiency in IL-4 had no substantial effect on lesion development in one study [41], but was associated with a decrease in atherosclerotic lesion formation in another work [42]. Prolonged hypercholesterolaemia in animal models of atherosclerosis is associated with enhanced IL-4 production, which has been proposed to have a proatherogenic effect [43]. Other Th2-related cytokines, IL-5 and IL-33, appear to exhibit antiatherogenic properties. IL-5 induced by a specific LDL subtype (malondialdehyde-LDL) activates immunoglobulin M (IgM) production by B1 cells, which confers a protective effect against atherosclerosis [44]. Another Th2 cytokine, IL-33, exhibits atheroprotective effects, at least in part, through induction of IL-5 and the production of IgM-type anti-oxLDL antibodies [45]. Moreover, mice deficient in serum IgM show accelerated atherosclerosis [46]. In humans, genetic variants in the vicinity of the IL-5 locus were strongly associated with coronary artery disease in 32,717 patients [47]. Furthermore, another publication showed that plasma IL-5 concentrations were inversely correlated with subclinical atherosclerosis [48], and two studies implicated raised IL-5 concentrations in unstable angina and myocardial infarction [49] and the risk of recurrent coronary artery disease events [50]. However, a more recent study showed that the relationships between plasma IL-5 and carotid intima-media thickness are weak [51]. Taken together, the involvement of the Th2 pathway in mouse models remains unclear, and its contribution to human cardiovascular diseases still needs to be investigated.

Treg response in atherosclerosis Regulatory T cells (Tregs) are subdivided into two types (natural and induced) depending on their origin. Natural Tregs, characterized by the expression of CD4, CD25 and the transcriptional factor FOXP3 (forkhead box/winged helix transcription factor), develop in the thymus, and

recognize specific self-antigens. These cells home to peripheral tissues to maintain self-tolerance, thereby preventing autoimmunity through inhibition of pathogenic lymphocytes. In humans, mutation of the FOXP3 gene is involved in IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome, which is characterized by immune dysregulation and the development of autoimmune diseases [52]. Induced Tregs (iTregs) are generated in the periphery during an active immune response. Naïve CD4+ CD25— cells in the periphery can be converted, in the presence of TGF-␤, IL-10 or low antigenic peptide, into CD4+ CD25+ (FOXP3+) cells. The iTregs induced by IL-10 are called Tr1 cells, whereas cells induced by TGF-␤ are called Th3 cells. These cells mediate suppressor function through the production of IL-10 and TGF-␤, respectively (reviewed in [53]). Both natural Tregs and iTregs are important for protection against atherosclerosis, either by direct effects on these T cells or through deactivation of dendritic cells. In mouse models, a deficiency in Tregs was associated with increased atherogenesis and lesion inflammation [54]. In addition, iTregs, including Tr1 and Th3, have protective roles in atherosclerosis through the production of IL-10 or TGF-␤ [55—58]. IL-10 is expressed in advanced human atherosclerotic plaques [59], and its high plasma concentration is associated with a more favourable prognosis in patients with acute coronary syndrome [60]. Mechanistically, IL-10 has been shown to inhibit metalloproteinase activity and to stimulate the production of TIMP-1 (tissue inhibitor of metalloproteinase) in human mononuclear phagocytes [61]. Concerning TGF-␤, its circulating concentration was decreased in patients with advanced atherosclerosis [62]. The concentration of circulating Tregs was decreased in patients with acute coronary syndromes, and their suppressive property was altered [63]. Collectively, these data show a clear antiatherogenic effect of Tregs, and of factors produced by these cells, such as IL-10 and TGF-␤.

Th17 response in atherosclerosis Apart from the Th1 and Th2 responses, the Th17 response represents a new lineage (for review [64,65]). Th17 cells produce, in addition to the major isoform IL-17 (or IL17A), other interleukins, such as IL-17F, IL-21 and IL-22. Besides Th17, other cells have the capacity to produce IL-17; these include ␥␦ T cells, natural killer cells, natural killer T cells and the newly identified lymphoid tissue inducer-like cells [66]. Th17 cell differentiation requires retinoid-related orphan receptor (ROR)␥t, which cooperates with other transcriptional factors to induce IL-17 expression. Many factors have been suggested to stimulate Th17 differentiation, such as IL-23, IL-6 and TGF-␤ (reviewed in [67]). Th17 cells have an important role in defence against extracellular bacteria and fungi, as revealed in hyperIgE patients, who are susceptible to Candida albicans and Staphylococcus aureus infections because of the absence of the Th17 response [68]. Besides this physiological role of Th17, these cells are involved in the development of a wide range of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis and inflammatory bowel disease (for review see [65]). Regarding the role of IL-17 in cardiovascular diseases, the results in mouse models were

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Inflammation in atherosclerosis controversial, depending on the mouse model used, the strategy used to block or supplement IL-17 or the time of the fat diet (reviewed in [69]). In humans, cells that express both IL-17 and interferon␥ were detected in patients with coronary atherosclerosis, and these cells were shown to enhance inflammation [70]. However, other studies suggested a stabilizing role for IL-17 expression in human lesions. We found that IL-17 expression in carotid plaques was associated with a lower macrophage content, but with a higher smooth muscle cell content and a fibrous plaque phenotype, suggesting a role for IL17 in promoting plaque stability [71]. Consistent with these data, Gistera et al. showed in human carotid plaques that expression of ROR␥t and expression of IL-17A were positively associated with profibrotic markers [72]. One of the possible protective effects of IL-17 may be related to its role in down-regulation of endothelial vascular cell adhesion protein 1 expression [71]. Consistent with this possibility, we further found that lower concentrations of circulating IL17 in 981 patients admitted for acute myocardial infarction were associated with a higher risk of major cardiovascular events, including all-cause death and recurrent myocardial infarction, after 2 years of follow-up [73]. Moreover, the highest risk of death and recurrent myocardial infarction was observed in patients with low concentrations of IL-17 and high concentrations of vascular cell adhesion protein 1, suggesting an important modulatory role for IL-17 in vascular inflammation. In this regard, it is noteworthy that major adverse cardiovascular events have been reported in psoriatic patients assigned to ustekinumab or briakinumab, two anti-p40 antibodies that block IL-23 (and IL-12); this was not the case for patients assigned to placebo or treated with etanercept, an inhibitor of TNF-␣ [74,75]. Lastly, the use of secukinumab, an anti-interleukin-17A monoclonal antibody, in 606 psoriatic patients, showed that four patients (all in the secukinumab group) had a stroke and two had a myocardial infarction [76]. Outcomes of future trials involving larger numbers of patients treated and followed for a much longer period are awaited. Until these data are available, patients with an identifiable high cardiovascular risk treated with inhibitors of the IL-17 pathway should be monitored closely for the development or progression of cardiovascular complications.

Role of B lymphocytes in atherosclerosis The first investigations into the role of B cells in atherosclerosis tended to show that they had atheroprotective effects [77,78]. However, these studies did not take into account B cell heterogeneity, in particular the existence of B1 and B2 cells. Concerning the role of B2 in atherosclerosis, the majority of studies seem to show that these cells have a proatherogenic effect (reviewed in [79]). In particular, anti-CD20 treatment, which leads preferentially to B2 cell depletion, while B1 cells remain nearly intact, reduced atherosclerosis [80]. The mechanisms involved in the proatherogenic effects of B2 cells are not clear, but may be related to the proatherogenic effects of IgG and IgE antibodies [79]. Consistent with these observations, circulating

5 oxLDL-IgG complexes have been correlated with coronary heart disease severity [81] and myocardial infraction [82]. Moreover, IgE antibodies have been shown to be elevated in patients with coronary heart disease compared with in healthy individuals [83], and were shown to be a prognostic marker for myocardial infarction in the Helsinki Heart Study [84]. The B1 cells that produce IgM antibodies have been shown to display a strong atheroprotective role [79]. In particular, OSE (oxidation specific epitopes)-IgM antibodies, which recognize antigenic determinants expressed on the surface of apoptotic cells and on oxLDL, inhibit foam cell formation and promote efferocytosis. A protective role for OSE-IgM antibodies is also supported by data in humans, showing that anti-oxLDL-specific IgM antibodies are inversely associated with cardiovascular disease adverse effects [85]. Thus, a therapeutic strategy to prevent atherosclerosis complications would be to reduce B2 cells while preserving or increasing B1 cells and IgM production. In this regard, exploiting existing therapeutic approaches that decrease B2 cell activation or survival may be a novel line of treatment for atherosclerosis and its complications. For example, the development of B cell-targeting therapeutics for rheumatoid arthritis and systemic lupus erythematosus has gained a lot of attention in recent years. Thus, it can be speculated that patients treated with rituximab (anti-CD20) or belimumab (anti-BAFF [B cell activating factor] blocks soluble BAFF from binding to its receptor, resulting in apoptosis of mature B2 cells) may also have a better outcome in terms of cardiovascular diseases.

Reducing inflammation as a therapeutic strategy As atherosclerosis is recognized to be a chronic inflammation of the arterial wall, several anti-inflammatory strategies for the prevention of atherosclerosis complications have been examined, mainly using animal models. To date, no clinical trial has addressed whether targeting the inflammation itself will reduce cardiovascular diseases. Of note, analysis of clinical studies, using traditional antiinflammatory therapies, revealed that these drugs do not have necessarily atheroprotective effects, which is a result of their ‘‘off-target’’ effects. Indeed, the cardioprotective effect of aspirin (50—150 mg daily) is more likely to be related to its antiplatelet effect rather than a direct anti-inflammatory intervention [86]. This is also the case for statins, which besides their cholesterol-lowering effects, exert anti-inflammatory effects [87]. Moreover, inhibitors of the cyclooxygenase-2 enzyme, which are known to exert anti-inflammatory effects, may contribute to increased cardiovascular morbidity as a result of the prothrombotic effect of inhibiting prostacyclin production [88]. Acute myocardial infarction is mainly a complication of atherosclerotic plaque rupture or erosion and coronary artery occlusion by a thrombus. Interruption of blood supply leads to the rapid death of cardiac myocytes in the ischaemic heart; this triggers an acute inflammatory response, which contributes to cardiac remodelling through the effect on extracellular matrix degradation/deposition

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as well as on the clearance of dead cardiomyocytes and their debris. Hence, a preferred outcome of the acute inflammatory response is successful resolution and repair of tissue damage, rather than persistence of inflammation, which can lead to scarring and loss of organ function. Then, anti-inflammatory strategies may have detrimental effects in case of acute myocardial infarction in atherosclerotic patients. Furthermore, an ideal anti-inflammatory therapy will promote anti-inflammatory cells, such as Tregs, and inhibit inflammatory pathways. Related to this, strategies based on vaccination or mucosal immunization with antigens from atherosclerotic plaques come under candidate therapeutic methods. Certain of these strategies lead to the induction of Tregs, which may inhibit pathogenic T cells and protect against atherosclerosis (reviewed in [89]). Thus, despite a large body of evidence, mainly in animal models, showing that lowering inflammation may be a promising strategy for decreasing atherosclerosis and its complications, this has yet to be proved in humans.

Disclosure of interest The author declares that she has no competing interest.

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Please cite this article in press as: Taleb S. Inflammation in atherosclerosis. Arch Cardiovasc Dis (2016), http://dx.doi.org/10.1016/j.acvd.2016.04.002