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Immune-mediated and lipid-mediated platelet function in atherosclerosis

Ahmadsei, Maiwanda,b; Lievens, Dirka; Weber, Christiana,b; von Hundelshausen, Philippa; Gerdes, Norberta

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Current Opinion in Lipidology: October 2015 - Volume 26 - Issue 5 - p 438-448
doi: 10.1097/MOL.0000000000000212
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Platelets are small, anuclear, megakaryocyte-derived discoid fragments of 2–3 μm in diameter. Apart from their classical function in thrombosis and hemostasis [1], it is now widely recognized that platelets have a significant function in inflammatory and immune responses [2,3,4▪,5▪,6–8]. After leaving the bone marrow platelets to circulate in the blood system macrophages in the liver and spleen will clear them in a period of 5–9 days [9–11]. Their classical role in thrombosis and hemostasis was recently reviewed in detail by several experts in the field [1,5▪,12▪,13]. Furthermore, recent studies implicated platelets as essential effectors in sepsis [14], experimental autoimmune encephalomyelitis [15], allergy, rheumatoid arthritis [16], host defense during bacterial infection [17], and cancer [18]. In addition to their role in these disease models, platelets display a particular versatile ability to modulate immune responses in atherosclerosis [19–22]. Specifically, platelets facilitate the recruitment of inflammatory cells to inflamed lesion sites and dysfunctional endothelium [23] by interacting with endothelial cells [24], circulating leukocytes [25,26] (monocytes [27], neutrophils [28,29], dendritic cells [30,31], and T cells [32]), and progenitor cells [33] (Fig. 1). This crosstalk induces leukocyte activation, adhesion, transmigration as well as formation of platelet–leukocytes aggregates (PLAs) [34,35]. Platelets contribute to atherosclerosis and modulate immune responses via various surface molecules [20] such as glycoproteins [36–44], costimulatory molecules (CD40,CD40L) [45–54], cell adhesion molecules (CAMS) (e.g. P-selectin) [55–59,60▪▪], junctional adhesion molecules (e.g. JAM-A) [61▪▪,62▪▪,63,64], Toll-like receptors (TLRs) [65–72], chemokine receptors [6,73▪], scavenger receptors [74], and protease-activated receptors (PARs) [20] (Fig. 1). In addition, platelets release upon activation considerable amounts of cytokines [e.g. interleukin-1 beta (IL-1β) [75,76] or transforming growth factor beta (TGF-β) [77,78]], chemokines (e.g. CXCL4 or CCL5) [73▪], and other contents [e.g. ADP, thromboxane A2 (TXA2), serotonin, platelet-derived growth factor (PDGF) [79], and soluble CD40 ligand (sCD40L) [46,80–83]] partly from preformed granules [22]. Emerging work suggests a strong link between thrombosis and innate immune cells, particularly monocytes, neutrophils, and dendritic cells. Innate immune cells can initiate and propagate fibrin formation, induce neutrophil extracellular trap (NET) formation (which comprise matrix DNA and histones), and trigger platelet activation during development of thrombosis [1,14,84–88] (Fig. 1). A recent study reported that neutrophils scan for activated platelets to transmigrate and initiate inflammation [60▪▪]. The concept of immunothrombosis, which is increasingly recognized as an independent line of host defense, is reviewed excellently by others [1].

Potential proatherogenic functions of platelets. Platelet activation, caused by various stimuli (e.g. oxLDL), leads to upregulation of several surface molecules, release of soluble mediators, and change of platelet morphology. Following adhesion, activated platelets interact with endothelial cells leading to subsequent recruitment of leukocytes and enhanced inflammation. Circulating platelets form platelet–leukocyte aggregates, which in turn recruit and activate other leukocytes. Adhesion of platelets to monocytes may promote the release of proinflammatory mediators. CD40 on neutrophils interacts with platelet CD40L and sCD40L resulting in ROS production. In addition, platelets directly bind to neutrophils and trigger the formation of NETs mediated via β-defensin secretion by platelets. Finally, CD40L-expressing T cells can activate platelets via the mechanisms that are not fully understood yet. 5-HT, Serotonin; ADP; CCL2, chemokine (C-C motif) ligand 2; CCL3, chemokine (C-C motif) ligand 3; CCL5, chemokine (C-C motif) ligand 5; CXCL4, chemokine (C-X-C motif) ligand 4; CXCL8, chemokine (C-X-C motif) ligand 8; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; MMPs, matrix metalloproteinases; NETs, neutrophil extracellular traps; oxLDL, oxidized low-density lipoprotein; ROS, reactive oxygen species; sCD40L, soluble CD40 ligand; sP-selectin, soluble P-Selectin; TXA2, thromboxane A2; VCAM-1, vascular cell adhesion molecule 1.

Since several overview articles recently discussed platelets under inflammatory conditions in general, this article highlights only a few topics of platelet biology in more detail. In particular, recent developments in specific platelet-signaling pathways (e.g. CD40-CD40L dyad, or JAM-A) as well as platelet–leukocyte crosstalk will be summarized. Furthermore, we will discuss direct effects of statins on platelets and interactions between lipid metabolism and platelets. Lastly, therapeutic options for the above-mentioned pathways and the role of platelets in novel cardiovascular imaging approaches will be considered.

Atherosclerosis is a chronic inflammatory disease of large-sized and medium-sized arteries, which is caused by complex immune and metabolic processes. Initial lipid accumulation, subsequent cellular activation inducing the recruitment of immune cells, transformation of monocytes into foam cells, and various immune reactions mediated by T cells, B cells, granulocytes, monocytes, and dendritic cells lead to a dysfunctional endothelium during an asymptomatic process which starts in childhood and progresses with age [19]. Atherosclerosis is the primary underlying cause of cardiovascular disease (CVD) such as ischemic heart disease and stroke. In 2011, CVD still accounted for 31.3% (786 641) of all 2.5 million deaths, or approximately one in every three deaths in the USA. Finally, in 2011 the estimated annual costs for CVD and stroke were $320.1 billion highlighting the economic burden in addition to the personal calamities [89].

In addition to leukocytes and vascular cells platelets contribute to atherosclerosis during all stages by secretion of chemokines [6,25,73▪,90▪,91] and other inflammatory mediators [20,92–94]. One of the most important functions of platelets during atherogenesis, apart from their role in coagulation, lies in the interaction with endothelial cells and leukocyte activation and recruitment [20].

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LDL cholesterol levels correlate with CVD [89,95,96]. Recent studies evidence a functional link between platelet biology and lipid metabolism [97▪▪]. Notably, the amount of platelet-bound oxidized LDL (oxLDL) is increased in patients with acute coronary syndromes [98]. Carnevale et al.[99▪] showed that platelets can oxidize LDL-particles in vitro via NADPH oxidase 2 (NOX2)-derived oxidative stress. OxLDL-particles in turn amplify platelet activation via receptors such as CD36, or lectin-like oxLDL receptor-1 (LOX-1) (Fig. 1). Interestingly, platelets of NOX2-hereditary deficient patients showed reduced oxLDL production compared with platelets from healthy individuals. NOX2 antagonists, CD36-blocking, or LOX1-blocking peptides inhibited platelet activation significantly. Stimulation with ‘ApoB100 danger-associated signal 1’, a native peptide derived from Apolipoprotein B-100 of LDL, induces platelet activation, degranulation, adhesion, and release of proinflammatory cytokines [100▪]. Platelets also mediate oxLDL-induced monocyte extravasation, platelet–monocyte aggregate (PMA) formation, and foam cell formation and enhance neutrophil transmigration. Of note, platelet inhibition by clopidogrel or aspirin is effective in reducing oxLDL uptake and PMA formation [101,102▪]. Platelet CD36 promotes atherosclerotic inflammatory processes through its interaction with oxLDL and is involved in thrombus formation following atherosclerotic plaque rupture [103]. Specific oxLDL-CD36 interactions induce platelet activation, upregulation of P-selectin, CD40L, and intraplatelet reactive oxygen species (ROS) [104]. Whole-body deficiency of CD36 in mice causes reduced atherosclerotic plaque formation [105,106].

3-Hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (statins), a drug class primarily used to lower plasma cholesterol concentrations in the prevention of myocardial infarction and stroke, can act as antithrombotic and reduce platelet activation via platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31)-signaling and decrease microparticle shedding from endothelium, platelets, and inflammatory cells [107–109]. Atorvastatin delays murine platelet activation and reduces thrombin generation and expression of tissue factor, P-selectin, and integrin αIIbβ3 on platelet-derived microparticles in patients with peripheral arterial occlusive disease [110,111]. In addition, atorvastatin can inhibit platelet CD40-mediated and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect [112]. Notably atorvastatin reduces the proadhesive and prothrombotic endothelial cell phenotype caused by cocaine consumption [113]. Atorvastatin enhances interactions between endothelial nitric oxide synthase (eNOS) and caveolin-1, thus increasing endothelial cell nitric oxide production [113]. In addition, statins can directly increase platelet nitric oxide production by upregulating platelet eNOS in turn inhibiting platelet recruitment. Furthermore, statins lower CXCL4 and CXCL7 plasma levels, inhibit signaling of the thrombin receptor PAR-4, and inhibit NOX2, which mediates oxidation of LDL particles by platelets [110,114–116]. Prior to simvastatin therapy hyperlipidemic patients show a significantly higher percentage of P-selectin-positive platelets and higher reactivity to thrombin compared with healthy control individuals. Simvastatin therapy reduces P-selectin expression on platelets and soluble P-selectin (sP-selectin) levels [117]. The ARMYDA-ACS (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) clinical trial showed that atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes (ACS) undergoing early percutaneous coronary intervention [118]. Sexton et al.[119▪] demonstrated that a high dose of rosuvastatin administered early can lead to significantly lower PLAs in patients with ACS. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial showed that atorvastatin reduces the risk of ischemic stroke and other cardiovascular events, however, treated patients displayed a higher risk of suffering intracranial hemorrhage. This side-effect, nonetheless, was not confirmed by others [120,121]. The acute benefits of statins in the setting of ACS might lead to an inclusion of high-dose statin therapy as a part of the standard of care for the initial management of ACS [122].

Several studies suggest that cholesterol efflux acts as a crucial regulator of myelopoiesis and atherogenesis [97▪▪,123,124,125▪,126,127]. Murphy et al.[128] were able to connect two seemingly separate research areas, platelet generation and cholesterol metabolism. The absence of ATP-binding cassette sub-family G member 4 (ABCG4), a cholesterol transporter highly expressed in bone marrow megakaryocyte progenitors, led to increased megakaryocyte production, thrombocytosis, and atherogenesis. ABCG4-deficient megakaryocyte progenitor cells showed defective cholesterol efflux accompanied by increased proliferation. Of note, cholesterol is a key component of cell membranes and in mammalian cells its metabolism is closely regulated by several feedback mechanisms to prevent dyslipidemia. ABCG4 in megakaryocytes prevents thrombocytosis via thrombopoietin (TPO)-TPO receptor (c-MPL) degradation thereby impairing c-MPL signaling (Fig. 2). In the absence of ABCG4 megakaryocyte progenitor cells showed an increased cell surface expression of c-MPL and reduced activity of the cholesterol-sensitive Src family kinase Lyn. The reduced activity of Lyn kinase caused an interruption of the negative-feedback loop suppressing c-MPL expression. Tolimidone, an allosteric Lyn kinase activator, in turn reduced c-MPL levels on ABCG4-deficient megakaryocyte progenitor cells. Interestingly, Murphy et al. showed that HDL infusions could reduce platelet counts in LDL receptor-deficient (Ldlr−/−) mice, suggesting that HDL infusions may offer a new approach to tackle thrombocytosis and atherothrombotic events. In addition lack of ABCB6, likewise highly expressed on megakaryocyte progenitor cells, leads to thrombocytosis, enhanced proinflammatory platelet activity, and accelerated atherosclerosis in Ldlr−/− mice. Furthermore, ABCB6 deficiency increased platelet counts and mean platelet volume. Platelets of Abcb6−/− mice contained more CCL5 which was paralleled by increased plasma CCL5 levels. Additionally, the number of PLAs in Abcb6−/− bone marrow-transplanted mice was increased, which resulted in enhanced leukocyte activation [129▪]. Taken together Murphy et al. showed that not only ABCG4, but also ABCB6 modulates thrombopoiesis and thus atherogenesis.

Role of ABCG4 and JAM-A in myelopoiesis and platelet activity. In megakaryocyte progenitor cells ABCG4 located on the Golgi apparatus promotes cholesterol efflux to HDL. ABCG4 also mediates inhibition of thrombopoietin (TPO)-TPO receptor (c-MPL) signaling by promoting c-MPL degradation. Absence of ABCG4 leads to increased megakaryocyte progenitor cell proliferation, which in turn promotes thrombocytosis and atherosclerosis. Junctional adhesion molecule A (JAM-A) deficiency in platelets enhances integrin αIIbβ3 ‘outside-in’ signaling. The absence of the cSrc-inhibiting kinase (CSK), which is recruited by JAM-A to the c-Src/αIIbβ3-complex causes elevated c-Src activity and subsequent platelet hyper-reactivity, adhesion, and degranulation, with increased secretion of chemokines (CXCL4 and CCL5) by platelets. Protein tyrosine phosphatase nonreceptor type 1 (PTPN1) dephosphorylates JAM-A and enhances platelet activation.


The JAM family is a subclass within the immunoglobulin (Ig) superfamily and mediates leukocyte-endothelial contact and regulates cell polarity [62▪▪,130,131]. JAM-C and JAM-A were initially identified on platelets [131]. In addition to expression on platelets [132], JAM-A is also found on endothelial cells [133], leukocytes [134], and CD34+ progenitor cells. JAM-A mediates cell polarity [3], leukocyte trafficking, and recruitment. Apart from that, JAM-A has a barrier function and modulates stem cell adhesion and differentiation [133,135–137]. On endothelial cells, JAM-A is a component of the tight junction and upon inflammatory stimuli (e.g. oxLDL) translocates from its baso-lateral position to the apical surface to interact with blood leukocytes [138,139]. The role of JAM-A appears highly cell-type specific. Total body JAM-A deficiency yields no significant effects on the extent of atherosclerosis. Although JAM-A on leukocytes protects from atherosclerosis, endothelial JAM-A promotes plaque formation by guiding leukocytes to sites of plaque development [62▪▪]. Recently, Karshovska et al.[61▪▪] showed increased atherosclerotic plaque formation in apolipoprotein E (ApoE)-deficient mice with platelet-specific inactivation JAM-A (trJama−/−Apoe−/−) compared with control (trJama+/+Apoe−/−) mice. Platelet JAM-A deficiency accelerated early-stage atherosclerosis corroborating a previously reported role of JAM-A in controlling activation of platelets [140,141]. Plasma levels of platelet-derived chemokines CCL5 and CXCL4 were elevated in trJama−/−Apoe−/− mice accompanied by increased capacity to bind neutrophils and monocytes [61▪▪]. In addition, lack of platelet JAM-A caused a prothrombotic phenotype, increased aggregation, and c-Src activation, which could be abolished by the inhibition of integrin αIIbβ3 signaling in vitro. Upon platelet activation JAM-A is phosphorylated [142,143], and in resting platelets JAM-A acts as an endogenous inhibitor of integrin αIIbβ3 by attenuating c-Src-dependent ‘outside-in’ signaling of integrin αIIbβ3 via recruitment of the c-Src-inhibiting kinase (CSK) [140,141,144]. Upon binding of αIIbβ3 by its ligand fibrinogen, JAM-A is dephosphorylated by protein tyrosine phosphatase nonreceptor type 1 (PTPN1) causing a CSK and JAM-A dissociation from the c-Src/αIIbβ3-complex (Fig. 2). Karshovska et al.[61▪▪] were also able to inhibit PTPN1, which is responsible for the dephosphorylation of JAM-A and enhanced platelet activation. Similar approaches might find their way into translational antithrombotic research in the future.


The CD40-CD40L dyad plays an important role in atherosclerosis [20,45,46] and neointima formation [145,146▪]. CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily [147] that is activated by CD40 ligand (CD40L, also known as CD154), a 39 kDa transmembrane glycoprotein and member of the TNF super family, which is present on human platelets at a rate of approximately 1600 copies/platelet [148]. CD40L also interacts with leukocyte integrin alpha M (Mac-1) [149,150] and can be shed as a truncated and soluble form (sCD40L, 18 kDa) [151]. CD40L is highly expressed on activated platelets which are the main source of sCD40L [48]. sCD40L is biologically active and binds CD40 as a trimeric ligand followed by activation of nuclear factor (NF)-κB and subsequent induction of inflammation [152–154]. CD40L shedding is mediated by matrix metalloproteinase 2 and 9, ADAM10 as well as integrin αIIbβ3 [155–158]. Elevated sCD40L levels are found in patients with CVD and may predict the presence and extent of ACS [81]. Inhibition of CD40 [159] or CD40L [160] not only reduces atherosclerotic plaque size but also yields a less inflammatory and more fibrotic plaque phenotype [161]. Furthermore, CD40L deficiency ameliorates adipose tissue inflammation in diet-induced obesity by increasing the number of regulatory T cells (Tregs), a T cell subset known to control inflammation and also to protect from atherosclerosis [53,162], in obese adipose tissue [163,164]. In contrast, CD40 deficiency aggravates adipose tissue inflammation and causes metabolic dysregulation [165▪]. Gavins et al.[166] showed that mice deficient in either CD40 or CD40L are protected against microvascular thrombosis after treatment with lipopolysaccharide (LPS). In brain arterioles, a CD40 deficiency will completely, whereas CD40L deficiency will only partially, prevent accelerated thrombosis induced by LPS administration. In venules, on the other hand, LPS-induced thrombus formation was completely prevented in Cd40l−/− mice, whereas CD40 deficiency provided no significant protection [166]. CD40 and CD40L are not only expressed on leukocytes but also on platelets, endothelial cells, and other cells present in the atherosclerotic plaque. Activated platelets bind via CD40L endothelial and leukocytic CD40 [48,49] (Fig. 1). The platelet–endothelium interaction can induce the release of prothrombotic mediators (e.g. tissue factor, TF), chemokines (e.g. CCL2 and CCL5), matrix metalloproteases (e.g. MMP-1, MMP-2, MMP-3, and MMP-9), and upregulation of adhesion molecules (e.g. VCAM-1 and ICAM-1) by endothelial cells (Fig. 1). Apart from the subsequent leukocyte recruitment and enhanced atherogenesis, interactions between platelet CD40L or sCD40L and endothelial CD40 can lead to reduced synthesis of nitric oxide by endothelial cells [50]. Huo et al.[57] first demonstrated that Apoe−/− mice receiving injection of activated platelets showed exacerbated atherosclerotic plaque formation in comparison with untreated Apoe−/− mice. We were able to demonstrate that injection of activated CD40L-deficient platelets into Apoe−/− mice prevents PLA formation and reduces atherogenesis when compared with transfusions of activated wild-type platelets [47]. Injection of activated CD40L-deficient platelets caused in contrast to the injection of wild-type platelets no decrease of Tregs. Moreover, we showed recently that platelet CD40L modulates thrombus growth through phosphatidylinositol 3-kinase β rather than via CD40 and IκB kinase α [167▪]. Others demonstrated that platelet bound or recombinant sCD40L stimulates human-cultured endothelial cells to release ultralarge vWF multimers, which are rapidly proteolyzed into smaller units [168].


Current antiplatelet therapies are mostly based on the direct modulation of platelet function via ADP receptor antagonists or inhibitors of cyclooxygenase (COX)-1, integrin αIIbβ3, and enzymes involved in the coagulation cascade [20,169–171]. Interestingly, a recent study failed to demonstrate a benefit of low-dose aspirin therapy for Japanese patients aged more than 60 years [172,173]. This and other studies illustrate the persisting need for alternative approaches to modulate platelet physiology and function. As already reported, inhibition of PTPN1 [61▪▪], which dephosphorylates JAM-A and enhances platelet activation, might provide a new alternative approach to control platelet activity. We showed that specific inhibition with small-molecule inhibitors [174] of CD40–TRAF6 (TNF receptor associated factor 6, an adaptor molecule involved in CD40 signaling) interaction improved insulin sensitivity, reduced adipose tissue inflammation, and decreased hepatosteatosis [175▪,176]. This effect on leukocytic target cells could be at least in part evoked by platelet-expressed CD40L. Accordingly targeted treatments of selective signaling pathways may constitute a promising strategy to reduce platelet-driven contribution to atherosclerosis without encountering thrombotic complications, which were observed in early clinical studies of systemic CD40/CD40L inhibition. Although many clinical trials of treatments that increase HDL, for example via CETP inhibitors torcetrapib and dalcetraoib or ER-niacin, failed [177–179], Murphy et al.[128] showed that recombinant HDL (rHDL) infusion reduced platelet counts in Ldlr−/− mice. HDL infusion may offer a new approach to treat thrombocytosis and reduce atherothrombotic events. The HDL infusion therapies in development are currently at a crossroad [180–183]. The potent CETP inhibitors evacetrapib and anacetrapib are currently in phase 3 trials for chronic cardiovascular risk reduction, reports are expected in 2015 and 2017. Apart from HDL injection, Murphy et al.[128] showed that oral application of tolimidone, an allosteric Lyn kinase activator, which decreases thrombopoietin receptor (c-MPL) expression on megakaryocyte progenitor cells, reduced thrombocytosis and atherogenesis. Therapeutic inhibition of ABCG4 [128] or ABCB6 [129▪] might provide a new alternative to treat patients with thrombocytopenia.

Recent findings show the potential role of platelets and immune cells in noninvasive cardiovascular imaging [184,185,186▪,187,188]. MRI approaches successfully identified atherosclerotic plaques in the carotid artery. In recent years, substantial advances were made in the development of targeted magnetic agents for cardiovascular imaging [189–192,193▪]. von Elverfeldt et al.[185] were able to image the extent of myocardial ischemia/reperfusion injury after coronary vessel occlusion using a contrast agent, consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against activated platelets, via MRI. Jacobin-Valat et al. used the Versatile UltraSmall SuperParamagnetic Iron Oxide (VUSPIO) platform, based on 7.5-nm-sized magnetic cores (maghemite γ-Fe2O3), that enhances contrast in MRI. VUSPIO conjugated to the humanized αIIbβ3 antibody rIgG4 TEG4 forms the TEG4-VUSPIO complex, which could selectively accumulate around activated platelets within atherosclerotic lesions. Despite potential challenges and limitations on the way (e.g. human antihuman antibody responses [194]) these efforts open a perspective to identify culprit locations of atherothrombotic activity.


In this article, we have described the versatile functions of platelets in atherosclerosis. The increasing recognition of platelets as immune modulators offers new possibilities beyond classical anticoagulation to target specific platelet–leukocyte and platelet–endothelium interactions to limit atherosclerosis. Recent findings furthermore clarify the direct impact of lipid metabolism and cholesterol metabolism on platelet physiology. The novel utilization of platelets in cardiovascular imaging shows the great potential of platelets beyond their former unspectacular role as ‘discoid fragments’ in biomedicine.


The authors thank Holger Winkels and Christina Bürger for critical editing of the manuscript.

Financial support and sponsorship

Research of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB1123-A5 to NG, SFB1123-A2 to PvH, and SFB1123-A1 & B4 to CW). MA is supported by a doctoral stipend from the Deutsches Zentrum für Herzkreislaufforschung (DZHK).

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

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  • ▪▪ of outstanding interest


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60▪▪. Sreeramkumar V, Adrover JM, Ballesteros I, et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346:1234–1238.

This outstanding article shows neutrophil scanning for activated platelets before transmigration.

61▪▪. Karshovska E, Zhao Z, Blanchet X, et al. Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ Res 2015; 116:587–599.

This article clarifies the mechanistical role of platelet JAM-A.

62▪▪. Schmitt MM, Megens RT, Zernecke A, et al. Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation 2014; 129:66–76.

This excellent article demonstrates the versatile functions of JAM-A on different cell types, particularily on edothelial cells.

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This is a very good and comprehensive review on platelet chemokines.

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90▪. Rossaint J, Herter JM, Van Aken H, et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 2014; 123:2573–2584.

The functional role of integrins in NET formation was shown in this study.

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97▪▪. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol 2015; 15:104–116.

This is an excellent, very recent article about cholesterol metabolism and inflammation.

98. Stellos K, Sauter R, Fahrleitner M, et al. Binding of oxidized low-density lipoprotein on circulating platelets is increased in patients with acute coronary syndromes and induces platelet adhesion to vascular wall in vivo – brief report. Arterioscler Thromb Vasc Biol 2012; 32:2017–2020.
99▪. Carnevale R, Bartimoccia S, Nocella C, et al. LDL oxidation by platelets propagates platelet activation via an oxidative stress-mediated mechanism. Atherosclerosis 2014; 237:108–116.

This article describes the oxidation of LDL by platelets in vitro.

100▪. Assinger A, Wang Y, Butler LM, et al. Apolipoprotein B100 danger-associated signal 1 (ApoBDS-1) triggers platelet activation and boosts platelet-leukocyte proinflammatory responses. Thromb Haemost 2014; 112:332–341.

This article demonstrated the direct effects of the innate-activating peptide ApoBDS-1 on platelets.

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102▪. Badrnya S, Schrottmaier WC, Kral JB, et al. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol 2014; 34:571–580.

This elegant article showed the role of platelets in monocyte transmigration.

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119▪. Sexton TR, Wallace EL, Macaulay TE, et al. The effect of rosuvastatin on platelet-leukocyte interactions in the setting of acute coronary syndrome. J Am Coll Cardiol 2015; 65:306–307.

This article examines direct effects of rosuvastatin in the setting of ACS on platelet-leukocyte biology.

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125▪. Murphy AJ, Dragoljevic D, Tall AR. Cholesterol efflux pathways regulate myelopoiesis: a potential link to altered macrophage function in atherosclerosis. Front Immunol 2014; 5:490.

This is a very good overview of cholesterol efflux and atherosclerosis.

126. Westerterp M, Bochem AE, Yvan-Charvet L, et al. ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ Res 2014; 114:157–170.
127. Westerterp M, Murphy AJ, Wang M, et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res 2013; 112:1456–1465.
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129▪. Murphy AJ, Sarrazy V, Wang N, et al. Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2014; 34:751–758.

This article elucidates the platelet-specific/megakaryocyte-specific role of ABCB6 in atherosclerosis.

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This article characterizes the versatile and complex character of the CD40–CD40L signalling cascade.

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163. Poggi M, Engel D, Christ A, et al. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice. Arterioscler Thromb Vasc Biol 2011; 31:2251–2260.
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165▪. Wolf D, Jehle F, Michel NA, et al. Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice. Circulation 2014; 129:2414–2425.

This excellent article demonstrated that CD40 surprizingly protects against obesity.

166. Gavins FN, Li G, Russell J, et al. Microvascular thrombosis and CD40/CD40L signaling. J Thromb Haemost 2011; 9:574–581.
167▪. Kuijpers MJ, Mattheij NJ, Cipolla L, et al. Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase beta, and Not Via CD40 and IkappaB Kinase alpha. Arterioscler Thromb Vasc Biol 2015; 35:1374–1381.

This article revealed CD40L-triggered but CD40-independent signaling in platelets.

168. Moller K, Adolph O, Koffler J, et al. Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells. Thromb Haemost 2015; 113:
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This outstanding article shows that specific CD40–TRAF6 inhibition can modulate insulin resistance.

176. van den Berg SM, Seijkens TT, Kusters PJ, et al. Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice. Int J Obes (Lond) 2015; 39:782–790.
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186▪. Megens RT, Bianchini M, Schmitt MM, Weber C. Optical imaging innovations for atherosclerosis research: multiphoton microscopy and optical nanoscopy. Arterioscler Thromb Vasc Biol 2015; 35:1339–1346.

This is a very good article focusing on multiphoton microscopy and optical nanoscopy in atherosclerosis.

187. Jayagopal A, Linton MF, Fazio S, Haselton FR. Insights into atherosclerosis using nanotechnology. Curr Atheroscler Rep 2010; 12:209–215.
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190. Jacobin-Valat MJ, Deramchia K, Mornet S, et al. MRI of inducible P-selectin expression in human activated platelets involved in the early stages of atherosclerosis. NMR Biomed 2011; 24:413–424.
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192. Saam T, Hatsukami TS, Takaya N, et al. The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imaging for characterization and assessment. Radiology 2007; 244:64–77.
193▪. Mulder WJ, Jaffer FA, Fayad ZA, Nahrendorf M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med 2014; 6:239sr1.

This excellent state-of-art article focuses on current imaging techniques in atherosclerosis.

194. Reichert JM. Antibodies to watch in 2014. MAbs 2014; 6:5–14.

atherosclerosis; atherothrombosis; inflammation; lipids; lipoproteins; platelets

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