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New Insights into the Role of Inflammation in the Pathogenesis of Atherosclerosis

Meng-Yu Wu, Chia-Jung Li, Ming-Feng Hou and 1 more

International Journal of Molecular Sciences · 2017 · Review · CC BY

doi:10.3390/ijms18102034

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, smooth muscle cell proliferation, cell apoptosis, necrosis, fibrosis, and local inflammation. Immune and inflammatory responses have significant effects on every phase of atherosclerosis, and increasing evidence shows that immunity plays a more important role in atherosclerosis by tightly regulating its progression. Therefore, understanding the relationship between immune responses and the atherosclerotic microenvironment is extremely important. This article reviews existing knowledge regarding the pathogenesis of immune responses in the atherosclerotic microenvironment, and the immune mechanisms involved in atherosclerosis formation and activation.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Atherosclerosis is a chronic inflammatory disease characterized by intense immunological activity. Atherosclerosis is widespread, and leads to morbidity and mortality along with the development of circulatory problems, including coronary artery disease and cerebrovascular disease. In the heart, atherosclerosis can cause myocardial infarction and heart failure due to coronary artery stenosis, and in the brain, the stenosis or rupture of atherosclerotic plaques leads to transient ischemic attacks, ischemic stroke, or hemorrhage stroke. If stenosis affects renal arterial branches, it can result in renal impairment and general hypertension. On other arterial branches of extremities, atherosclerosis can lead to peripheral arterial occlusion disease and critical limb ischemia. The formation of atherosclerotic plaques, which are characterized by the accumulation of lipids, local inflammation, smooth muscle cell (SMC) proliferation, cell apoptosis, necrosis, and fibrosis, is a major causative factor of arterial stenosis, and involves a chronic inflammatory response initiated by endothelial damage and inflammatory cell activation. This review article summarizes current knowledge regarding the role of immunity in atherosclerosis and, in particular, the pathogenesis of human atherosclerosis. The atherosclerotic microenvironment and mechanisms associated with immune responses to atherosclerosis are also discussed in detail.

2.1. Roles of Lipid Metabolism in Atherosclerosis

Cholesterol, triglycerides, and lipoproteins are implicated in atherosclerosis pathogenesis. Increased serum low-density lipoprotein (LDL) and triglyceride concentrations are responsible for the formation of atherosclerotic lesions. The roles of lipid metabolism and LDL modification are important for atherosclerosis development. Lipid metabolism occurs via exogenous and endogenous pathways. The exogenous pathway begins with chylomicron synthesis and secretion by the intestine. Chylomicrons contain apolipoproteins (Apos) B-48, C-II, and E. The Apo C-II is an essential cofactor of lipoprotein lipase (LPL) transport of fatty acids to adipose tissue. After LPL activity, the chylomicron remnant is relatively enriched in cholesterol due to the loss of triacylglycerol, and absorbed into the liver by Apo E. The endogenous pathway begins with the synthesis of very LDL (VLDL) particles, which are triglyceride-rich and contain Apo B-100, C-II, and E. After removal of the triglycerides to adipose tissue, a portion of VLDL remnants are metabolized to LDL particles that transport cholesterol esters and lesser amounts of triglycerides. Small LDL particles penetrate the endothelial barrier and deposit in the extracellular matrix of subendothelial spaces by Apo B-100 binding to proteoglycans, which are among the most important molecules for lipoprotein retention. Retention of LDL particles in the vessel wall is considered the first step in atherosclerosis pathogenesis.

2.2. LDL Modification and Oxidization in Atherosclerosis

In the second step of atherosclerosis pathogenesis, subendothelial LDL is oxidized by resident vascular cells, and triggers vascular-cell production of monocyte chemoattractant protein-1 (MCP-1) and macrophage colony stimulating factors (M-CSFs). Under smoking, hypertension, hyperglycemia, and hyperlipidemia status, the production of reactive oxygen species (ROS) is increased, and overwhelms the endogenous antioxidant response. The oxidative stress increases LDL oxidation and impairs endothelial function. Chronic oxidative stress is a stronger risk of atherosclerosis formation. In the initial phase of LDL modification, the lipid components are interacted with ROS, and produce many types of lipid oxidation products. The lipid oxidation products, such lysophospholipid products, attack with the Apo B protein. Apo B are oxidized, and lead to changes in the amino acid side chains by breaking peptide bonds. After modification of Apo B, oxidized LDL (ox-LDL) becomes a ligand of scavenger receptors. The retention of ox-LDL is recognized, and interacts with two major scavenger receptors on macrophages: class A scavenger receptors (SR) AI/II, and class B scavenger receptor cluster of differentiation 36 (CD36). The SRAI/II recognizes the modification of Apo B protein on ox-LDL, and oxidized phospholipids are recognized by CD36. After interaction with scavenger receptors, the macrophages are activated and uptake ox-LDL.

Ox-LDL also induces several pro-inflammatory conditions via a lectin-like oxidized LDL receptor-1 (LOX-1). The chemotactic activity from the oxidative modification of LDL stimulates monocyte binding to endothelial cells, thereby increasing the adhesive properties of the endothelium, including the overexpression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Inflammatory cells and monocytes subsequently release MCP-1 to activate leukocytes in the media and stimulate the proliferation of SMCs. The monocytes differentiate into macrophages with the expression of scavenger receptors (SRs), including SR-AI/II, SR-BI, CD36, LOX-1, and Toll-like receptors (TLRs), and lead to lipid accumulation. Ox-LDL–CD36 interaction induces increased ox-LDL internalization and activates additional macrophages (Figure 1). Recently reported data support ox-LDL participation in not only macrophage activation, but also retention. Moreover, macrophages induce inflammation progression via interleukin (IL)-1β, tumor necrosis factor (TNF), reactive oxygen species (ROS), and metalloproteases.

Ox-LDLs also increase the expression of growth factors, including platelet-derived growth factor for migration and basic fibroblast growth factor, for proliferation on SMCs. SMC proliferation contributes to the thickening of atherosclerotic plaques and the formation of a necrotic core. Activation of inflammatory cytokines and ox-LDL influence extracellular matrix remodeling and cause lesion thinning by increasing matrix metalloproteinase (MMP)-1 and -9 expression. During LDL oxidation, β-cleavage reactions modulated by ROS lead to the formation of aldehydic end products, which are considered important toxic messengers and cause oxidative stress injury in vessel walls. The stress response induces SMC apoptosis via p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. Finally, ox-LDL–CD36 interaction also induces P-selectin expression and the activation of integrin αIIbβ3 in resting platelets, causing platelet aggregation and activation via Src kinases and Rho kinase signaling pathways. The activated platelets express LOX-1 to mediate adhesion to endothelial cells, and LOX-1 expression enhances endothelin-1 (ET-1) release. Endothelial function is impaired along with decreased nitric oxide (NO) production and increased prostaglandin synthesis. According to previous reports, ox-LDL also plays a key role in atherosclerosis progression.

3. Endothelial Function and Microenvironment

Vascular endothelium plays a key role in the regulation of vascular tone, as well as regulation of vascular SMC (VSMC) proliferation, vascular fibrinolysis, and adhesion and migration of inflammatory cells by secreting numerous substances, including NO, ET-1, prostaglandin, endothelium-derived hyperpolarizing factor, thromboxane A2, and angiotensin II. Endothelial dysfunction is a primary step in atherosclerosis development. In early stage atherosclerosis, oxidative stress can originate from hyperlipidemic states, diabetes mellitus, smoking, or hypertension due to the accumulation of advanced glycation end products (AGEs), which causes endothelial damage by activating cytokines and increasing LDL retention via a macrophage–SR pathway. A dysfunctional endothelium also accelerates ROS generation and induces local inflammation. The dysfunction of vascular–tone balance is noted by increased ET-1 and decreased NO. A series of pathophysiologic changes and mechanism are discussed later.

3.1. Roles of NO in Atherosclerosis

NO is a potent oxidant that regulates vascular tone, blood-pressure homeostasis, fibrinolysis, and resting-platelet and leukocyte adhesion. NO also plays a protective role by inhibiting the abnormal proliferation of VSMCs. NO is produced from the conversion of l-arginine from endothelial cells to l-citrulline. The activity of the enzyme, nicotinamide adenine dinucleotide phosphate (NADPH)-dependent NO synthase (NOS), is mediated by calcium, flavin adenine dinucleotide, flavin mononucleotide, and tetrahydrobiopterin (BH4) as cofactors. Current studies support two pathways for the endothelial isoform of NOS (eNOS) in atherogenesis. Under physiological conditions, BH4, an antiatherogenic molecule in tissue, regulates eNOS activity to activate NO production. However, under hypertension, hypercholesterolemia, smoking, and diabetes mellitus conditions, enhance oxidative stress oxidizes BH4, leading to BH4 deficiency. Lower BH4 levels in tissue induces the uncoupling of NOS and superoxide, causing endothelial-cell damage (Figure 2).

In endothelial cells, BH4 concentration plays an important role in NO synthesis. BH4 is synthesized from three pathways that regulate its production and degradation. First, BH4 is produced from guanosine 5′-triphosphate (GTP) by GTP cyclohydrolase I. Second, BH4 can be synthesized from quinonoid dihydrobiopterin (BH2), which is the natural product from the oxidation of BH4, through a salvage pathway. Third, BH4 can be also synthesized from sepiapterin, which is an oxidized BH4 analogue, by enzymatic reduction of sepiapterin reductase and dihydrofolate reductase. During pro-atherosclerosis conditions, the activity of GTP cyclohydrolase I decreases through ox-LDL accumulation, and BH4 bioavailability can be rapidly reduced by ROS and oxidized via the BH3 radical to BH2. Additionally, Kruppel-like factor 2 is inhibited by inflammatory cytokines and causes expression of VCAM-1, the endothelial adhesion molecule, and promotes laminar shear stress in endothelial cells.

3.2. Role of ET-1 in Atherosclerosis

ET-1 is a 21-amino acid peptide that regulates vasoconstriction, inflammation, and the proliferation of endothelial cells by interactions with NO. ET-1 expression is induced by TNF-α, tumor growth factor (TGF)-β, IL-1, ox-LDL, angiotensin II, and hypoxia, and regulated by several transcription factors, including activator protein 1, hypoxia-inducible factor-1, vascular endothelial zinc finger 1, and GATA-binding protein 2. ET-1 is formed by ET-converting enzymes and expressed in several cells, including endothelial cells, VSMCs, and macrophages. Two ET-receptor subtypes (ETA and ETB) have been previously reported, with endothelial cells harboring ETB receptors, and SMCs and macrophages expressing both receptors on the cell surface. ET-1 binds to ETA receptors on VSMCs to induce vasoconstriction, and ETB receptors on endothelial cells for vasodilatation by release of NO. ET-1 expression can be both inhibited and stimulated by eNOS. In atherosclerotic arteries, ox-LDL stimulates the release and enhanced tissue levels of ET-1 in endothelial cells, VSMCs, and inflammatory cells. High concentrations of ET-1 induce the expression of endothelial cell adhesion molecules and promote monocyte migration and activation regulated by MCP-1. Additionally, ET-1 stimulates VSMC proliferation, cytokine, and superoxide production in macrophages. After foam cell formation, local inflammation and ROS increase to facilitate lesion development. In such circumstances, foam cells produce ET-1, which can act on macrophages by binding to ETB receptors (Figure 2).

4. Roles of Immune-Mediator Regulation

The early phase of atherosclerosis is considered an inflammatory response to ox-LDL. In this phase, hypercholesterolemia conditions increase LDL infiltration and retention, leading to the activation of endothelial and inflammatory cells by the release of pro-inflammatory factors. The expression of leukocyte adhesion molecules causes leukocyte infiltration and adhesion, after which leukocytes release chemoattractant stimuli, including chemokines. MCP-1 attracts leukocytes harboring chemokine receptor (CCR)-2, including monocytes and T and B cells. Interferon (IFN)-γ-inducible protein 10 (or C-X-C motif chemokine 10 (CXCL10)), IFN-inducible T cell α-chemoattractant (or CXCL11), monokines induced by IFN-γ (Mig or CXCL9) selectively attract T and B lymphocytes bearing CXC receptor CXCR3. The fractalkine CX3CL1, which is a membrane-bound chemokine, also promotes CX3CR1+ monocytes. Macrophages are major players in initial inflammation and innate immune responses.

4.1. Macrophages

Following exposure to chemoattractants and chemokines, monocytes become tethered via interactions between monocyte P-selectin glycoprotein 1 with endothelial P-selectins. For adhesion and diapedesis, monocytes express the integrin very late antigen-4 and lymphocyte function-associated antigen-1 to bind to endothelial cell ligands, including VCAM-1 and ICAM-1. These monocytes differentiate into macrophages via monocyte colony stimulating factor (M-CSF) mediators. Macrophages use pattern-recognition receptors (PRRs), including SRs and TLRs, such as the transmembrane proteins SR-A (CD204), CD36, macrophage receptor with collagenous structure, and LOX-1 (OLR-1), to mediate the internalization of endotoxins, apoptotic bodies, and LDL particles. After activation, monocytes differentiate to two main phenotypes of macrophages: M1 and M2 macrophages. Both inflammatory M1 and regulatory M2 macrophages are found in atherosclerotic lesions. M1 macrophages contribute to inflammation by secreting pro-inflammatory cytokines after intake of modified LDL and presenting antigen to T cells via PRRs, resulting in the release of pro-inflammatory cytokines, including IL-1, IL-6, IL-12, IL-15, IL-18, MIF, and TNF-α, to activate T cells. M2 macrophages have anti-inflammatory functions to resolve plaque inflammation by efferocytosis and releasing Th2 cytokines, such as IL-4, IL-10, and IL-13 (Figure 3).

In atherosclerotic lesion, the TGF-β from macrophages plays a role in vascular biology by affecting cell proliferation, differentiation, migration, adhesion, apoptosis, and extracellular matrix production. TGF-β regulates both vasodilation and vasoconstriction via the TGF-β/ALK5/Smad3 pathway, inducing the expression of ET-1 on endothelial cells, and decreasing endothelial cell migration and proliferation. However, TGF-β has a dual role in atherosclerosis. It had a pro-atherosclerotic function by increasing VSMC proliferation; while the anti-atherosclerotic processes from TGF-β involve reducing inflammatory cell recruitment, platelet adhesion, and macrophage activation. Instead of either totally pro- or antiatherogenic function, TGF-β is demonstrated as having bifunctional effects on atherosclerosis.

TLRs also bind molecules and initiate a signaling cascade promoting macrophage activation to produce inflammatory cytokines, proteases, and cytotoxic oxygen- and nitrogen-radical molecules. Similar activities occur in dendritic cells (DCs), mast cells, and endothelial cells, which also harbor TLRs. Vascular endothelial growth factor is also released from macrophages and promotes angiogenesis. Cholesterol accumulation occurs in macrophages following ox-LDL uptake by SRs, including CD36, SR-A1, and LOX-1. The cholesterol esters are hydrolyzed, and ox-LDL molecules are catabolyzed by macrophage endosomes and lysosomes. In the endoplasmic reticulum, acyl coenzyme A cholesterol acyltransferase-1 esterifies the free cholesterol and stores it in lipid droplets. In atherosclerosis, lipid homoeostasis in macrophages is disrupted, causing the formation of foam cells. The apoptosis of foam cells is induced by prolonged endoplasmic reticulum stress due to their ineffective clearance by macrophages. This results in secondary cell necrosis, which subsequently forms a necrotic core. Macrophages trigger apoptosis in SMCs by activating the FAS apoptotic pathway and secreting proapoptotic TNF-α and NO. Macrophages also decrease collagen synthesis in SMCs and degrade various types of extracellular matrix via macrophage-derived MMPs, especially MMP-2 and -9. SMC death and a weakened extracellular matrix causes the rupture of atherosclerotic lesions, and the exposure of the thrombogenic material causes platelet adhesion and aggregation.

4.2. Dendritic Cells

Several studies support DCs as key modulators of immune responses and critical mediators of antigen presentation in atherosclerosis. DCs are a family of antigen-presenting cells that express high levels of major histocompatibility complex class II (MHC II) molecules and link innate and adaptive immune responses by presenting endogenous and exogenous antigens to T cells. The life cycle of DCs involves three stages. In bone marrow, common dendritic precursor cells differentiate to classical DCs (cDCs) via FMS-like tyrosine kinase 3 (FLT3) and FLT3 ligand (FLT3L) signaling. cDCs differentiate into either lymphoid CD8+ or nonlymphoid CD103+ cDCs via activity associated with basic leucine zipper transcription factor ATF-like 3, interferon regulatory factor 8, and the inhibitor of DNA protein 2. In lymphoid tissue, CD8+/CD103+ cDCs are critical to the development of CD8+ DCs by cross-presentation of antigens to CD8+ T cells. CD4+/CD103+ cDCs also present antigen to CD4+ T cells. In nonlymphoid tissue, CD11b+ DCs are functionally similar to lymphoid CD4+/CD103+ cDCs, based on the expression of common macrophage markers, including signal-regulatory protein-α and F4/80.

In atherosclerotic lesions, DCs are tethered to the activated endothelium with the help of adhesion molecules, including P-selectin, E-selectin, and VCAM-1. After the uptake of lipids and other antigens, DCs mature and present antigens in the context of co-stimulatory molecules, such as CD40, OX40L, CD80, and CD86. In lymphoid organs, DCs present the antigen to T cells and natural killer (NK) T cells in the context of MHC I, MHC II, or CD1d. TLR interactions in DCs enhance antigen presentation and stimulate the production of a variety of inflammatory cytokines, including IL-6, TNF, IL-12, IL-23, and granulocyte M-CSF (Figure 3). Foam cells are phagocytized by macrophages or immature DCs, and after lipid uptake and efferocytosis, this leads to DC foam-cell formation. The inflammatory cells emigrate from the vessel wall to clear apoptotic cell debris and foam cells. Mature CD11b+ DCs silence regulatory T cells activated by ox-LDL, pathogen-associated molecular pattern, and/or damage-associated molecular pattern-related stress. DCs and T cell-derived IFNs induce inflammatory macrophages, DCs, and effector CD4+ T cell sensitization. Additionally, ox-LDL downregulates CCR7 expression and decreases the emigration rate of DCs. CCL17-producing DCs also inhibit regulatory T cells. This cycle increases foam cell retention, apoptosis, and necrosis.

4.3. T Cells

T cells are recruited to the atherosclerotic lesion in a similar mechanism as that of monocytes via several of the same adhesion molecules and chemokines. Most of these T cells are TCRαβ+ CD4+ cells found in human atherosclerotic plaques as compared with CD8+ or TCRγδ+ T cells. T cells are activated by antigens presented from macrophages and DCs via two signals. First, ligations of the antigen receptor on the surface of antigen-presenting cells (APCs) initiate a response to pathogen-associated molecular patterns (PAMPs), which are molecules associated with pathogens. The MHC molecules interact with PAMPs, such as ox-LDL, microbial antigens, and heat shock proteins (HSP 60), which contribute to protect cells from stress damage expressed by stressed endothelial cells. Second, the ligation of the co-stimulatory molecule CD28 to T cells allows interactions with CD80 or CD86 on APCs. Additionally, T cells are also activated by interactions between CD40-ligand (CD40L or CD154) and CD40 on APCs, such as macrophages, B cells, DCs, endothelial cells, and SMCs. Early T lymphocyte activation protein-1 is an important stimulator of T helper cell 1 (Th1) differentiation, and is expressed by macrophages, endothelial cells, and SMCs in atherosclerotic lesions. Th1 also promotes IL-12 expression, which is also a stimulator of Th1 differentiation. Th1 cytokines, including IFN-γ, IL-2, and TNF-α and -β, activate macrophages, endothelial cells, and SMCs and cause local inflammation. IFN-γ is a proatherogenic cytokine and growth inhibitor of endothelial cells and SMCs that also induces the production of inflammatory lipid mediators through their expression of secretory phospholipase A2. After arterial injury, SMCs are inhibited by IFN-γ secreted from T cells, which causes atherosclerotic plaque destabilization and rupture. Additionally, IFN-γ augments TNF and IL-1 synthesis, which are powerful inflammatory inducers and indirectly inhibit the proliferation of SMCs and endothelial cells. Th1 cells activate signaling cascades related to pro-inflammatory cytokine expression, and macrophages are stimulated to secrete IL-1. These cascades involve the expression of TNF-α and IL-1 through -6. T cell cytokine expression causes the production of IL-6, which stimulates large amounts of acute-phase reactants, such as C-reactive protein, serum amyloid A, and fibrinogen, and results in local inflammation shifting to systemic reactions. The level of Th2-specific cytokine activity is lower than that from Th1 in atherosclerotic lesions, possibly due to local IL-12 secretion and IL-10 regulation. Cross-regulation of Th1 and Th2 occurs through IL-10 inhibition of the Th1 pathway, with IL-12 as an inhibitor of the Th2 pathway. Although Th2-related cytokines are involved in anti-inflammatory activity, they also induce elastolytic enzymes to promote the aneurysm formation (Figure 3).

4.4. Other Cells in Atherosclerosis

CD8+ T cells are a subpopulation of activated T cells that exhibit cytotoxic activity. In atherosclerotic lesions, after recognition of a foreign antigen from APCs, CD8+ T cells promote cell apoptosis via cytotoxic attack. NK T cells are a minor T cell subpopulation that are activated by lipid antigens and recognized by CD1 molecules on APC surfaces. Recent studies support NK T cells promoting increases in the formation of atherosclerotic plaques. After activation by glycolipid recognition by CD1, NK T cells product Th1 cytokines, such as IFN-γ and TNF-α, and release granzymes and perforin to promote apoptosis (Figure 3).

Mast cells and B cells are less frequently found in atherosclerotic lesions. Mast cells are classically involved in allergic and host defense responses. After activation, mast cells release pro-inflammatory cytokines and proteolytic enzymes, which contribute to atherogenesis. Mast cell interactions with APCs promote the production of TNF-α, INF-γ, and IL-6. Large concentrations of tryptase, chymase, the 5-lipoxygenase product leukotriene B4, and granulocyte M-CSF are released from mast cells in atherosclerotic lesions, leading to lesion destabilization and increased Th1 and Th2 responses. Additionally, activated mast cells correlate with higher levels of apoptosis, vascular leakage, and intraplaque hemorrhage and rupture.

Recent studies investigated the role of B cells in atherosclerosis. B cells are activated by foreign antigens via the B cell receptor, and B1 lymphocytes produce natural antibodies specific for ox-LDL, including Immunoglobulin M (IgM) antibodies, which might exhibit atheroprotective functions. The B2 subset of B cells, which is independent of Th1 cells, releases IgG2a and IgG1. Additionally, B cells also produce IL-10, which do not specifically affect Th1 or Th2 responses. Although some antibody reactions to atherosclerosis have been investigated in mice, B cell biology in human forms of the disease remains uncertain.

5. Plaque Rupture and Platelet Activation

Apoptotic cells in atherosclerotic lesions are ineffectively cleared by defective efferocytosis in macrophages, leading to secondary necrosis and the formation of the necrotic core. The release of pro-inflammatory stimuli—including proteases, cytokines, and prothrombotic factors—from inflammatory cells increases collagen degradation or decreases collagen synthesis by SMCs and promotes the destabilization of atherosclerotic lesions. Macrophages also activate the FAS apoptotic pathway and release TNF-α and NO to induce SMCs apoptosis. Macrophage-derived MMPs from macrophages and endothelial cells can weaken the fibrous cap, the rupture of which causes the exposure of thrombogenic material, which contributes to platelet aggregation and activation.

After disruption of the endothelium, platelets are recruited and tethered to activated endothelium via the interaction of platelet glycoprotein (GP) Ib-V-IX and von Willebrand factor (vWF). The platelets attach to the subendothelial matrix via GPVI, which acts as a collagen receptor and forms a complex with the receptor Fcγ. The VWF forms a complex with the GPIb-IX complex, which is associated via the platelet-adhesion mechanism. After adhesion, platelets upregulate formation with the GPIIb-IIIa complex of stable platelet aggregates by binding multiple ligands, including fibrinogen, vWF, fibronectin, and vitronectin. After stable adhesion, the platelets are activated and induce intracellular calcium flux to release α granules and dense granules, including 5-hydroxytryptamine, adenosine diphosphate, and adenosine triphosphate, for amplification of the platelet response. The α-granules include thromboxane A2, leukotriene B4 (LTB4), and a variety of pro-inflammatory mediators, which affect SMCs, endothelial cells, and promote cross-talk between monocytes and macrophages. The release of IL-1β and expression of CD-40L induce endothelial cells to produce IL-6, IL-8, MCP-1, and ROS, as well as the upregulation of leukocyte-adhesion molecules. The cytokine cascade and LTB4 contribute to the release of chemoattractants and the promotion of monocyte differentiation and neutrophil activation, as well as the monocyte release of chemokines, enhanced cyclooxygenase expression, and overproduction of prostaglandin E2 and I2. After platelet stable adhesion, the thrombus may encroach into the vessel lumen and cause the ischemia or infarction.

Another less common substrate for coronary thrombosis, plaque erosion, consists of a fibrous cap with lower cholesterol and a small or absent lipid core. It is characterized by abundant surface smooth muscle cells and proteoglycans. The mechanisms of plaque erosion are unclear. Current studies promote a hypothesis that the expression of TLR2 on endothelial cells may interact with Gram-positive toxins and hyaluronan, triggering endothelial dysfunction via ROS and cell apoptosis signaling. The endothelial damage may induce local inflammation and recruit neutrophils to attack endothelial cells. Neutrophils are activated and release proteases to damage endothelial cells. After endothelial cell detachment, the exposure of the subendothelial matrix leads to thrombus formation. Although plaque rupture and erosion may be caused via different mechanisms, both events may lead to infarction and ischemia due to the stenosis of vessel lumen.

Current drugs for controlling atherosclerosis majorly target the lipid metabolism and platelet activation pathway, such as station and aspirin. In particular, the statins regulate LDL metabolism and dramatically decrease the mortality and mobility of acute coronary syndrome. Nevertheless, mortality and mobility rates for acute coronary syndrome and stroke remain high in Westernized societies. Current studies support the hypothesis that inflammatory effector mechanisms play a critical role in atherosclerosis by the release of cytokines and inflammatory cell infiltration, leading to plaque rupture, erosion, thrombosis, acute coronary syndrome, and stroke. The anti-inflammatory drugs are new weapons to slow down the progression and development of cardiovascular disease. Although the detailed mechanisms are unclear, anti-inflammatory properties represent a promising new target against atherosclerosis.

6. Conclusions

In this review, we presented research associated with the roles of inflammatory cells and cytokines in atherosclerotic plaque initiation and progression. Numerous principles presented here are worth reiterating. First, hyperlipidemic status causes ox-LDL accumulation as the first step in atherosclerosis progression. Second, endothelial dysfunction impairs the regulation of vascular tone by increasing ET-1 levels and decreasing NO levels. Finally, macrophages play an important role in the inflammatory response, and following their activation, are involved with other immune cells in the advanced atherosclerotic lesion. The complicated mechanisms associated with inflammatory responses related to atherosclerosis remain largely unclear. This review provides an overview of recent studies of inflammatory responses related to atherosclerosis and offers a strong foundation for therapeutic interventions.

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    Cyrus T., Witztum J.L., Rader D.J., Tangirala R., Fazio S., Linton M.F., Funk C.D. Disruption of the 12/15-Lipoxygenase Gene Diminishes Atherosclerosis in Apo E-Deficient Mice. J. Clin. Investig. 1999;103:1597-1604.

    Not in our library10.1172/jci5897

  22. 22.

    Nagy L., Tontonoz P., Alvarez J.G., Chen H., Evans R.M. Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARγ. Cell. 1998;93:229-240.

    Not in our library10.1016/s0092-8674(00)81574-3

  23. 23.

    Park Y.M. CD36 Modulates Migration of Mouse and Human Macrophages in Response to Oxidized LDL and May Contribute to Macrophage Trapping in the Arterial Intima. J. Clin. Investig. 2009;119:136-145.

    Not in our library10.1172/jci35535

  24. 24.

    Park Y.M., Drazba J.A., Vasanji A., Egelhoff T., Febbraio M., Silverstein R.L. Oxidized LDL/CD36 Interaction Induces Loss of Cell Polarity and Inhibits Macrophage Locomotion. Mol. Biol. Cell. 2012;23:3057-3068.

    Not in our library10.1091/mbc.e11-12-1051

  25. 25.

    Hansson G.K., Robertson A.K., Soderberg-Naucler C. Inflammation and Atherosclerosis. Annu. Rev. Pathol. 2006;1:297-329.

    Not in our library10.1146/annurev.pathol.1.110304.100100

  26. 26.

    Liao F., Andalibi A., deBeer F.C., Fogelman A.M., Lusis A.J. Genetic Control of Inflammatory Gene Induction and NF-κB-Like Transcription Factor Activation in Response to an Atherogenic Diet in Mice. J. Clin. Investig. 1993;91:2572-2579.

    Not in our library10.1172/jci116495

  27. 27.

    Kohno M., Yokokawa K., Yasunari K., Minami M., Kano H., Hanehira T., Yoshikawa J. Induction by Lysophosphatidylcholine, a Major Phospholipid Component of Atherogenic Lipoproteins, of Human Coronary Artery Smooth Muscle Cell Migration. Circulation. 1998;98:353-359.

    Not in our library10.1161/01.cir.98.4.353

  28. 28.

    Lindner V., Lappi D.A., Baird A., Majack R.A., Reidy M.A. Role of Basic Fibroblast Growth Factor in Vascular Lesion Formation. Circ. Res. 1991;68:106-113.

    Not in our library10.1161/01.res.68.1.106

  29. 29.

    Stiko-Rahm A., Hultgardh-Nilsson A., Regnstrom J., Hamsten A., Nilsson J. Native and Oxidized LDL Enhances Production of PDGF AA and the Surface Expression of PDGF Receptors in Cultured Human Smooth Muscle Cells. Arterioscler. Thromb. 1992;12:1099-1109.

    Not in our library10.1161/01.atv.12.9.1099

  30. 30.
    The Role of Oxidized Low-Density Lipoproteins in Atherosclerosis: The Myths and the Facts · 2013
    No notice
  31. 31.

    Loidl A., Claus R., Ingolic E., Deigner H.P., Hermetter A. Role of Ceramide in Activation of Stress-Associated MAP Kinases by Minimally Modified LDL in Vascular Smooth Muscle Cells. Biochim. Biophys. Acta. 2004;1690:150-158.

    Not in our library10.1016/j.bbadis.2004.06.003

  32. 32.

    Rajavashisth T.B., Liao J.K., Galis Z.S., Tripathi S., Laufs U., Tripathi J., Chai N.N., Xu X.P., Jovinge S., Shah P.K., et al. Inflammatory Cytokines and Oxidized Low Density Lipoproteins Increase Endothelial Cell Expression of Membrane Type 1-Matrix Metalloproteinase. J. Biol. Chem. 1999;274:11924-11929.

    Not in our library10.1074/jbc.274.17.11924

  33. 33.

    Xu X.P., Meisel S.R., Ong J.M., Kaul S., Cercek B., Rajavashisth T.B., Sharifi B., Shah P.K. Oxidized Low-Density Lipoprotein Regulates Matrix Metalloproteinase-9 and Its Tissue Inhibitor in Human Monocyte-Derived Macrophages. Circulation. 1999;99:993-998.

    Not in our library10.1161/01.cir.99.8.993

  34. 34.

    Podrez E.A., Byzova T.V., Febbraio M., Salomon R.G., Ma Y., Valiyaveettil M., Poliakov E., Sun M., Finton P.J., Curtis B.R., et al. Platelet CD36 Links Hyperlipidemia, Oxidant Stress and a Prothrombotic Phenotype. Nat. Med. 2007;13:1086-1095.

    Not in our library10.1038/nm1626

  35. 35.

    Wraith K.S., Magwenzi S., Aburima A., Wen Y., Leake D., Naseem M.K. Oxidized Low-Density Lipoproteins Induce Rapid Platelet Activation and Shape Change through Tyrosine Kinase and Rho Kinase-Signaling Pathways. Blood. 2013;122:580-589.

    Not in our library10.1182/blood-2013-04-491688

  36. 36.

    Chen M., Kakutani M., Naruko T., Ueda M., Narumiya S., Masaki T., Sawamura T. Activation-Dependent Surface Expression of LOX-1 in Human Platelets. Biochem. Biophys. Res. Commun. 2001;282:153-158.

    Not in our library10.1006/bbrc.2001.4516

  37. 37.
    LOX-1, OxLDL, and Atherosclerosis · 2013
    No notice
  38. 38.

    Cominacini L., Pasini A.F., Garbin U., Pastorino A., Rigoni A., Nava C., Davoli A., Cascio V.L., Sawamura T. The Platelet-Endothelium Interaction Mediated by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Reduces the Intracellular Concentration of Nitric Oxide in Endothelial Cells. J. Am. Coll. Cardiol. 2003;41:499-507.

    Not in our library10.1016/s0735-1097(02)02811-5

  39. 39.

    Kakutani M., Masaki T., Sawamura T. A Platelet–Endothelium Interaction Mediated by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1. Proc. Natl. Acad. Sci. USA. 2000;97:360-364.

    Not in our library10.1073/pnas.97.1.360

  40. 40.

    Li L.X., Chen J.X., Liao D.F., Yu L. Probucol Inhibits Oxidized-Low Density Lipoprotein-Induced Adhesion of Monocytes to Endothelial Cells by Reducing P-Selectin Synthesis in Vitro. Endothelium. 1998;6:1-8.

    Not in our library10.3109/10623329809053400

  41. 41.

    Thorin E., Hamilton C.A., Dominiczak M.H., Reid J.L. Chronic Exposure of Cultured Bovine Endothelial Cells to Oxidized LDL Abolishes Prostacyclin Release. Arterioscler. Thromb. 1994;14:453-459.

    Not in our library10.1161/01.atv.14.3.453

  42. 42.

    Yu M., Tsai S.F., Kuo Y.M. The Therapeutic Potential of Anti-Inflammatory Exerkines in the Treatment of Atherosclerosis. Int. J. Mol. Sci. 2017;18:1260.

    Not in our library10.3390/ijms18061260

  43. 43.

    Uribarri J., Woodruff S., Goodman S., Cai W., Chen X., Pyzik R., Yong A., Striker G.E., Vlassara H. Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet. J. Am. Diet. Assoc. 2010;110:911-916.

    Not in our library10.1016/j.jada.2010.03.018

  44. 44.

    Orekhov A.N., Bobryshev Y.V., Sobenin I.A., Melnichenko A.A., Chistiakov D.A. Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease. Int. J. Mol. Sci. 2014;15:12807.

    Not in our library10.3390/ijms150712807

  45. 45.
    Endothelial Dysfunction in Chronic Inflammatory Diseases · 2014
    No notice
  46. 46.

    Wang D., Wang Z., Zhang L., Wang Y. Roles of Cells from the Arterial Vessel Wall in Atherosclerosis. Mediat. Inflamm. 2017.

    Not in our library10.1155/2017/8135934

  47. 47.

    Napoli C., de Nigris F., Williams-Ignarro S., Pignalosa O., Sica V., Ignarro L.J. Nitric Oxide and Atherosclerosis: An Update. Nitric Oxide. 2006;15:265-279.

    Not in our library10.1016/j.niox.2006.03.011

  48. 48.

    Ignarro L.J., Napoli C. Novel Features of Nitric Oxide, Endothelial Nitric Oxide Synthase, and Atherosclerosis. Curr. Atheroscler. Rep. 2005;5:17-23.

    Not in our library10.1007/s11892-005-0062-8

  49. 49.

    Moncada S., Higgs A. The L-Arginine-Nitric Oxide Pathway. N. Engl. J. Med. 1993;329:2002-2012.

    Not in our library10.1056/nejm199312303292706

  50. 50.

    Stuehr D.J. Mammalian Nitric Oxide Synthases. Biochim. Biophys. Acta. 1999;1411:217-230.

    Not in our library10.1016/s0005-2728(99)00016-x

  51. 51.

    Moncada S., Palmer R.M., Higgs E.A. Nitric Oxide: Physiology, Pathophysiology, and Pharmacology. Pharmacol. Rev. 1991;43:109-142.

    Not in our library

  52. 52.

    Nathan C., Xie Q.W. Regulation of Biosynthesis of Nitric Oxide. J. Biol. Chem. 1994;269:13725-13728.

    Not in our library

  53. 53.

    Kawashima S., Mitsuhiro Y. Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2004;24:998-1005.

    Not in our library10.1161/01.atv.0000125114.88079.96

  54. 54.

    Laursen J.B., Somers M., Kurz S., McCann L., Warnholtz A., Freeman B.A., Tarpey M., Fukai T., Harrison D.G. Endothelial Regulation of Vasomotion in ApoE-Deficient Mice: Implications for Interactions between Peroxynitrite and Tetrahydrobiopterin. Circulation. 2001;103:1282-1288.

    Not in our library10.1161/01.cir.103.9.1282

  55. 55.

    Lunte C.E., Kissinger P.T. Determination of Quinonoid Dihydrobiopterin by Liquid Chromatography and Electrochemical Detection. J. Chromatogr. 1984;317:407-412.

    Not in our library10.1016/s0021-9673(01)91680-2

  56. 56.

    Vann L.R., Payne S.G., Edsall L.C., Twitty S., Spiegel S., Milstien S. Involvement of Sphingosine Kinase in TNF-α-Stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells. J. Biol. Chem. 2002;277:12649-12656.

    Not in our library10.1074/jbc.m109111200

  57. 57.

    SenBanerjee S., Lin Z., Atkins G.B., Greif D.M., Rao R.M., Kumar A., Feinberg M.W., Chen Z., Simon D.I., Luscinskas F.W., et al. KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation. J. Exp. Med. 2004;199:1305-1315.

    Not in our library10.1084/jem.20031132

  58. 58.

    Fan J., Unoki H., Iwasa S., Watanabe T. Role of Endothelin-1 in Atherosclerosis. Ann. N. Y. Acad. Sci. 2000;902:84-94.

    Not in our library10.1111/j.1749-6632.2000.tb06303.x

  59. 59.

    Pernow J., Shemyakin A., Bohm F. New Perspectives on Endothelin-1 in Atherosclerosis and Diabetes Mellitus. Life Sci. 2012;91:507-516.

    Not in our library10.1016/j.lfs.2012.03.029

  60. 60.

    Sakurai T., Yanagisawa M., Masaki T. Molecular Characterization of Endothelin Receptors. Trends Pharmacol. Sci. 1992;13:103-108.

    Not in our library10.1016/0165-6147(92)90038-8

  61. 61.

    Schiffrin E.L., Touyz R.M. Vascular Biology of Endothelin. J. Cardiovasc. Pharmacol. 1997;32:S2-S13.

    Not in our library

  62. 62.

    Yanagisawa M., Masaki T. Molecular Biology and Biochemistry of the Endothelins. Trends Pharmacol. Sci. 1989;10:374-378.

    Not in our library10.1016/0165-6147(89)90011-4

  63. 63.

    Böhm F., Pernow J. The Importance of Endothelin-1 for Vascular Dysfunction in Cardiovascular Disease. Cardiovasc. Res. 2007;76:8-18.

    Not in our library10.1016/j.cardiores.2007.06.004

  64. 64.

    Ito H., Hirata Y., Adachi S., Tanaka M., Tsujino M., Koike A., Nogami A., Murumo F., Hiroe M. Endothelin-1 Is an Autocrine/Paracrine Factor in the Mechanism of Angiotensin II-Induced Hypertrophy in Cultured Rat Cardiomyocytes. J. Clin. Investig. 1993;92:398-403.

    Not in our library10.1172/jci116579

  65. 65.

    Iwasa S., Fan J., Shimokama T., Nagata M., Watanabe T. Increased Immunoreactivity of Endothelin-1 and Endothelin B Receptor in Human Atherosclerotic Lesions. A Possible Role in Atherogenesis. Atherosclerosis. 1999;146:93-100.

    Not in our library10.1016/s0021-9150(99)00134-3

  66. 66.

    Ivanova E.A., Orekhov A.N. The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis. Int. J. Mol. Sci. 2016;17:193.

    Not in our library10.3390/ijms17020193

  67. 67.

    Filep J.G., Sirois M.G., Foldes-Filep E., Rousseau A., Plante G.E., Fournier A., Yano M., Sirois P. Enhancement by Endothelin-1 of Microvascular Permeability Via the Activation of ETA Receptors. Br. J. Pharmacol. 1993;109:880-886.

    Not in our library10.1111/j.1476-5381.1993.tb13657.x

  68. 68.

    Swerlick A.R., Lawley T.J. Role of Microvascular Endothelial Cells in Inflammation. J. Investig. Dermatol. 1993;100:S111-S115.

    Not in our library10.1038/jid.1993.33

  69. 69.

    Hansson G.K. Inflammation, Atherosclerosis, and Coronary Artery Disease. N. Engl. J. Med. 2005;352:1685-1695.

    Not in our library10.1056/nejmra043430

  70. 70.

    Kume N., Cybulsky M.I., Gimbrone M.A. Lysophosphatidylcholine, a Component of Atherogenic Lipoproteins, Induces Mononuclear Leukocyte Adhesion Molecules in Cultured Human and Rabbit Arterial Endothelial Cells. J. Clin. Investig. 1992;90:1138-1144.

    Not in our library10.1172/jci115932

  71. 71.

    Dai G., Kaazempur-Mofrad M.R., Natarajan S., Zhang Y., Vaughn S., Blackman B.R., Kamm R.D., Garcia-Cardena G., Gimbrone M.A. Distinct Endothelial Phenotypes Evoked by Arterial Waveforms Derived from Atherosclerosis-Susceptible and -Resistant Regions of Human Vasculature. Proc. Natl. Acad. Sci. USA. 2004;101:14871-14876.

    Not in our library10.1073/pnas.0406073101

  72. 72.

    Boring L., Gosling J., Cleary M., Charo I.F. Decreased Lesion Formation in CCR2-/- Mice Reveals a Role for Chemokines in the Initiation of Atherosclerosis. Nature. 1998;394:894-897.

    Not in our library10.1038/29788

  73. 73.

    Gu L., Okada Y., Clinton S.K., Gerard C., Sukhova G.K., Libby P., Rollins B.J. Absence of Monocyte Chemoattractant Protein-1 Reduces Atherosclerosis in Low Density Lipoprotein Receptor-Deficient Mice. Mol. Cell. 1998;2:275-281.

    Not in our library10.1016/s1097-2765(00)80139-2

  74. 74.

    Haley K.J., Lilly C.M., Yang J.H., Feng Y., Kennedy S.P., Turi T.G., Thompson J.F., Sukhova G.H., Libby P., Lee R.T. Overexpression of Eotaxin and the CCR3 Receptor in Human Atherosclerosis: Using Genomic Technology to Identify a Potential Novel Pathway of Vascular Inflammation. Circulation. 2000;102:2185-2189.

    Not in our library10.1161/01.cir.102.18.2185

  75. 75.

    Mach F., Sauty A., Iarossi A.S., Sukhova G.K., Neote K., Libby P., Luster A.D. Differential Expression of Three T Lymphocyte-Activating CXC Chemokines by Human Atheroma-Associated Cells. J. Clin. Investig. 1999;104:1041-1050.

    Not in our library10.1172/jci6993

  76. 76.

    Lesnik P., Haskell C.A., Charo I.F. Decreased Atherosclerosis in CX3CR1-/- Mice Reveals a Role for Fractalkine in Atherogenesis. J. Clin. Investig. 2003;111:333-340.

    Not in our library10.1172/jci15555

  77. 77.

    Hansson G.K. Immune Mechanisms in Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2001;21:1876-1890.

    Not in our library10.1161/hq1201.100220

  78. 78.

    Mestas J., Ley K. Monocyte-Endothelial Cell Interactions in the Development of Atherosclerosis. Trends Cardiovasc. Med. 2008;18:228-232.

    Not in our library10.1016/j.tcm.2008.11.004

  79. 79.

    Moore K.J., Tabas I. Macrophages in the Pathogenesis of Atherosclerosis. Cell. 2011;145:341-355.

    Not in our library10.1016/j.cell.2011.04.005

  80. 80.

    Rizzacasa B., Morini E., Pucci S., Murdocca M., Novelli G., Amati F. LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies. Int. J. Mol. Sci. 2017;18:290.

    Not in our library10.3390/ijms18020290

  81. 81.

    Kruth H.S. The Fate of Lipoprotein Cholesterol Entering the Arterial Wall. Curr. Opin. Lipidol. 1997;8:246-252.

    Not in our library10.1097/00041433-199710000-00002

  82. 82.

    Alberts-Grill N., Timothy L.D., Rezvan A., Jo H. The Role of the Vascular Dendritic Cell Network in Atherosclerosis. Am. J. Phys. 2013;305:C1-C21.

    Not in our library10.1152/ajpcell.00017.2013

  83. 83.

    Hansson G.K., Robertson A.K. TGF-β in Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2004;24:e137-e138.

    Not in our library10.1161/01.atv.0000130728.38755.09

  84. 84.

    Grainger D.J. Transforming Growth Factor β and Atherosclerosis: So Far, So Good for the Protective Cytokine Hypothesis. Arterioscler. Thromb. Vasc. Biol. 2004;24:399-404.

    Not in our library10.1161/01.atv.0000114567.76772.33

  85. 85.

    Xu S., Liu A.C., Gotlieb A.I. Common Pathogenic Features of Atherosclerosis and Calcific Aortic Stenosis: Role of Transforming Growth Factor-β. Cardiovasc. Pathol. 2010;19:236-247.

    Not in our library10.1016/j.carpath.2009.09.007

  86. 86.

    Grainger D.J. TGF-β and Atherosclerosis in Man. Cardiovasc. Res. 2007;74:213-222.

    Not in our library10.1016/j.cardiores.2007.02.022

  87. 87.

    McCaffrey T.A. TGF-βs and TGF-β Receptors in Atherosclerosis. Cytokine. Growth. Factor. Rev. 2000;11:103-114.

    Not in our library10.1016/s1359-6101(99)00034-9

  88. 88.

    Falck-Hansen M., Christina K., Claudia M. Toll-Like Receptors in Atherosclerosis. Int. J. Mol. Sci. 2013;14:14008-14023.

    Not in our library10.3390/ijms140714008

  89. 89.

    Galkina E., Ley K. Immune and Inflammatory Mechanisms of Atherosclerosis. Annu. Rev. Immunol. 2009;27:165-197.

    Not in our library10.1146/annurev.immunol.021908.132620

  90. 90.

    Van Vré E.A., Van Brussel I., Bosmans J.M., Vrints C.J., Bult H. Dendritic Cells in Human Atherosclerosis: From Circulation to Atherosclerotic Plaques. Mediat. Inflamm. 2011.

    Not in our library10.1155/2011/941396

  91. 91.

    Aliberti J., Schulz O., Pennington D.J., Tsujimura H., e Sousa C.R., Ozato K., Sher A. Essential Role for ICSBP in the in vivo Development of Murine CD8α+ Dendritic Cells. Blood. 2003;101:305-310.

    Not in our library10.1182/blood-2002-04-1088

  92. 92.

    Hacker C., Kirsch R.D., Ju X.S., Hieronymus T., Gust T.C., Kuhl C., Jorgas T., Kurz S.M., Rose-John S., Yokota Y., et al. Transcriptional Profiling Identifies ID2 Function in Dendritic Cell Development. Nat. Immunol. 2003;4:380-386.

    Not in our library10.1038/ni903

  93. 93.

    Hashimoto D., Miller J., Merad M. Dendritic Cell and Macrophage Heterogeneity in vivo. Immunity. 2011;35:323-335.

    Not in our library10.1016/j.immuni.2011.09.007

  94. 94.

    Hildner K., Edelson B.T., Purtha W.E., Diamond M., Matsushita H., Kohyama M., Calderon B., Schraml B.U., Unanue E.R., Diamond M.S., et al. BATF3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity. Science. 2008;322:1097-1100.

    Not in our library10.1126/science.1164206

  95. 95.

    Schiavoni G., Mattei F., Sestili P., Borghi P., Venditti M., Morse H.C., Belardelli F., Gabriele L. ICSBP Is Essential for the Development of Mouse Type I Interferon-Producing Cells and for the Generation and Activation of CD8α+ Dendritic Cells. J. Exp. Med. 2002;196:1415-1425.

    Not in our library10.1084/jem.20021263

  96. 96.

    Tailor P., Tamura T., Morse H.C., Ozato K. The BXH2 Mutation in IRF8 Differentially Impairs Dendritic Cell Subset Development in the Mouse. Blood. 2008;111:1942-1945.

    Not in our library10.1182/blood-2007-07-100750

  97. 97.

    Subramanian M., Tabas I. Dendritic Cells in Atherosclerosis. Semin Immunopathol. 2014;Volume 36:93-102.

    Not in our library10.1007/s00281-013-0400-x

  98. 98.

    Niessner A., Weyand C.M. Dendritic Cells in Atherosclerotic Disease. Clin. Immunol. 2010;134:25.

    Not in our library10.1016/j.clim.2009.05.006

  99. 99.

    Koltsova E.K., Ley K. How Dendritic Cells Shape Atherosclerosis. Trends Immunol. 2011;32:540-547.

    Not in our library10.1016/j.it.2011.07.001

  100. 100.

    Zernecke A. Dendritic Cells in Atherosclerosis: Evidence in Mice and Humans. Arterioscler. Thromb. Vasc. Biol. 2015;35:763-770.

    Not in our library10.1161/atvbaha.114.303566

  101. 101.

    Tabas I. Macrophage Death and Defective Inflammation Resolution in Atherosclerosis. Nat. Rev. Immunol. 2010;10:36-46.

    Not in our library10.1038/nri2675

  102. 102.

    Maganto-Garcia E., Tarrio M.L., Grabie N., Bu D.X., Lichtman A.H. Dynamic Changes in Regulatory T Cells Are Linked to Levels of Diet-Induced Hypercholesterolemia. Circulation. 2011;124:185-195.

    Not in our library10.1161/circulationaha.110.006411

  103. 103.

    Weber C., Meiler S., Döring Y., Koch M., Drechsler M., Megens R.T., Rowinska Z., Bidzhekov K., Fecher C., Ribechini E., et al. CCL17-Expressing Dendritic Cells Drive Atherosclerosis by Restraining Regulatory T Cell Homeostasis in Mice. J. Clin. Investig. 2011;121:2898-2910.

    Not in our library10.1172/jci44925

  104. 104.

    Jonasson L., Holm J., Skalli O., Bondjers G., Hansson G.K. Regional Accumulations of T Cells, Macrophages, and Smooth Muscle Cells in the Human Atherosclerotic Plaque. Arteriosclerosis. 1986;6:131-138.

    Not in our library10.1161/01.atv.6.2.131

  105. 105.

    Kleindienst R., Xu Q., Willeit J., Waldenberger F.R., Weimann S., Wick G. Immunology of Atherosclerosis. Demonstration of Heat Shock Protein 60 Expression and T Lymphocytes Bearing α/β or γ/δ Receptor in Human Atherosclerotic Lesions. Am. J. Pathol. 1993;142:1927-1937.

    Not in our library

  106. 106.

    Stemme S., Holm J., Hansson G.K. T Lymphocytes in Human Atherosclerotic Plaques Are Memory Cells Expressing CD45RO and the Integrin VLA-1. Arterioscler. Thromb. 1992;12:206-211.

    Not in our library10.1161/01.atv.12.2.206

  107. 107.

    Van der Wal A.C., Das P.K., van de Berg D.B., van der Loos C.M., Becker A.E. Atherosclerotic Lesions in Humans. in situ Immunophenotypic Analysis Suggesting an Immune Mediated Response. Lab. Investig. 1989;61:166-170.

    Not in our library

  108. 108.

    Wick G., Jakic B., Buszko M., Wick M.C., Grundtman C. The Role of Heat Shock Proteins in Atherosclerosis. Nat. Rev. Cardiol. 2014;11:516-529.

    Not in our library10.1038/nrcardio.2014.91

  109. 109.

    Libby P., Ridker P.M., Maseri A. Inflammation and Atherosclerosis. Annu. Rev. Pathol. 2002;1:297-329.

    Not in our library10.1146/annurev.pathol.1.110304.100100

  110. 110.

    Ashkar S., Weber G.F., Panoutsakopoulou V., Sanchirico M.E., Jansson M., Zawaideh S., Rittling S.R., Denhardt D.T., Glimcher M.J., Cantor H. Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity. Science. 2000;287:860-864.

    Not in our library10.1126/science.287.5454.860

  111. 111.

    Giachelli C.M., Bae N., Almeida M., Denhardt D.T., Alpers C.E., Schwartz S.M. Osteopontin Is Elevated During Neointima Formation in Rat Arteries and Is a Novel Component of Human Atherosclerotic Plaques. J. Clin. Investig. 1993;92:1686-1696.

    Not in our library10.1172/jci116755

  112. 112.

    O’Brien E.R., Garvin M.R., Stewart D.K., Hinohara T., Simpson J.B., Schwartz S.M., Giachelli C.M. Osteopontin Is Synthesized by Macrophage, Smooth Muscle, and Endothelial Cells in Primary and Restenotic Human Coronary Atherosclerotic Plaques. Arterioscler. Thromb. 1994;14:1648-1656.

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    Uyemura K., Demer L.L., Castle S.C., Jullien D., Berliner J.A., Gately M.K., Warrier R.R., Pham N., Fogelman A.M., Modlin R.L. Cross-Regulatory Roles of Interleukin (IL)-12 and IL-10 in Atherosclerosis. J. Clin. Investig. 1996;97:2130-2138.

    Not in our library10.1172/jci118650

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    Peilot H., Rosengren B., Bondjers G., Hurt-Camejo E. Interferon-γ Induces Secretory Group IIA Phospholipase A2 in Human Arterial Smooth Muscle Cells. Involvement of Cell Differentiation, STAT-3 Activation, and Modulation by Other Cytokines. J. Biol. Chem. 2000;275:22895-22904.

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    Friesel R., Komoriya A., Maciag T. Inhibition of Endothelial Cell Proliferation by γ-Interferon. J. Cell Biol. 1987;104:689-696.

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    Hansson G.K., Hellstrand M., Rymo L., Rubbia L., Gabbiani G. Interferon γ Inhibits both Proliferation and Expression of Differentiation-Specific α-Smooth Muscle Actin in Arterial Smooth Muscle Cells. J. Exp. Med. 1989;170:1595-1608.

    Not in our library10.1084/jem.170.5.1595

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    Hansson G.K., Holm J. Interferon-Γ Inhibits Arterial Stenosis after Injury. Circulation. 1991;84:1266-1272.

    Not in our library10.1161/01.cir.84.3.1266

  118. 118.

    Szabo S.J., Sullivan B.M., Peng S.L., Glimcher L.H. Molecular Mechanisms Regulating Th1 Immune Responses. Annu. Rev. Immunol. 2003;21:713-758.

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    Gewurz H., Zhang X.H., Lint T.F. Structure and Function of the Pentraxins. Curr. Opin. Immunol. 1995;7:54-64.

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    Ikeda U., Ikeda M., Seino Y., Takahashi M., Kano S., Shimada K. Interleukin 6 Gene Transcripts Are Expressed in Atherosclerotic Lesions of Genetically Hyperlipidemic Rabbits. Atherosclerosis. 1992;92:213-218.

    Not in our library10.1016/0021-9150(92)90280-t

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    Loppnow H., Libby P. Proliferating or Interleukin 1-Activated Human Vascular Smooth Muscle Cells Secrete Copious Interleukin 6. J. Clin. Investig. 1990;85:731-738.

    Not in our library10.1172/jci114498

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    Mallat Z., Heymes C., Ohan J., Faggin E., Leseche G., Tedgui A. Expression of Interleukin-10 in Advanced Human Atherosclerotic Plaques: Relation to Inducible Nitric Oxide Synthase Expression and Cell Death. Arterioscler. Thromb. Vasc. Biol. 1999;19:611-616.

    Not in our library10.1161/01.atv.19.3.611

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    Binder C.J., Hartvigsen K., Chang M.K., Miller M., Broide D., Palinski W., Curtiss L.K., Corr M., Witztum J.L. IL-5 Links Adaptive and Natural Immunity Specific for Epitopes of Oxidized LDL and Protects from Atherosclerosis. J. Clin. Investig. 2004;114:427-437.

    Not in our library10.1172/jci200420479

  124. 124.

    Shimizu K., Shichiri M., Libby P., Lee R.T., Mitchell R.N. Th2-Predominant Inflammation and Blockade of IFN-γ Signaling Induce Aneurysms in Allografted Aortas. J. Clin. Investig. 2004;114:300-308.

    Not in our library10.1172/jci200419855

  125. 125.

    Geng Y.J., Henderson L.E., Levesque E.B., Muszynski M., Libby P. Fas Is Expressed in Human Atherosclerotic Intima and Promotes Apoptosis of Cytokine-Primed Human Vascular Smooth Muscle Cells. Arterioscler. Thromb. Vasc. Biol. 1997;17:2200-2208.

    Not in our library10.1161/01.atv.17.10.2200

  126. 126.

    Major A.S., Wilson M.T., McCaleb J.L., Su Y.R., Stanic A.K., Joyce S., van Kaer L., Fazio S., Linton M.F. Quantitative and Qualitative Differences in Proatherogenic NKT Cells in Apolipoprotein E-Deficient Mice. Arterioscler. Thromb. Vasc. Biol. 2004;24:2351-2357.

    Not in our library10.1161/01.atv.0000147112.84168.87

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    Melian A., Geng Y.J., Sukhova G.K., Libby P., Porcelli S.A. Cd1 Expression in Human Atherosclerosis. A Potential Mechanism for T Cell Activation by Foam Cells. Am. J. Pathol. 1999;155:775-786.

    Not in our library10.1016/s0002-9440(10)65176-0

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    Paulsson G., Zhou X., Tornquist E., Hansson G.K. Oligoclonal T Cell Expansions in Atherosclerotic Lesions of Apolipoprotein E-Deficient Mice. Arterioscler. Thromb. Vasc. Biol. 2000;20:10-17.

    Not in our library10.1161/01.atv.20.1.10

  129. 129.

    Tupin E., Nicoletti A., Elhage R., Rudling M., Ljunggren H.G., Hansson G.K., Berne G.P. CD1D-Dependent Activation of NKT Cells Aggravates Atherosclerosis. J. Exp. Med. 2004;199:417-422.

    Not in our library10.1084/jem.20030997

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    Bot I., de Jager S.C., Zernecke A., Lindstedt K.A., van Berkel T.J., Weber C., Biessen E.A. Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E–Deficient Mice. Circulation. 2007;115:2516-2525.

    Not in our library10.1161/circulationaha.106.660472

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    Lindstedt K.A., Mäyränpää M.I., Kovanen P.T. Mast Cells in Vulnerable Atherosclerotic Plaques—A View to a Kill. J. Cell Mol. Med. 2007;11:739-758.

    Not in our library10.1111/j.1582-4934.2007.00052.x

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    Lee M., Calabresi L., Chiesa G., Franceschini G., Kovanen P.T. Mast Cell Chymase Degrades ApoE and ApoA-II in ApoA-I–Knockout Mouse Plasma and Reduces Its Ability to Promote Cellular Cholesterol Efflux. Arterioscler. Thromb. Vasc. Biol. 2002;22:1475-1481.

    Not in our library10.1161/01.atv.0000029782.84357.68

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    Sun J., Sukhova G.K., Wolters P.J., Yang M., Kitamoto S., Libby P., MacFarlane L.A., Clair J.M., Shi G.P. Mast Cells Promote Atherosclerosis by Releasing Proinflammatory Cytokines. Nat. Med. 2007;13:719-724.

    Not in our library10.1038/nm1601

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    Binder C.J., Shaw P.X., Chang M.K., Boullier A., Hartvigsen K., Horkko S., Miller Y.I., Woelkers D.A., Corr M., Witztum J.L. The Role of Natural Antibodies in Atherogenesis. J. Lipid Res. 2005;46:1353-1363.

    Not in our library10.1194/jlr.r500005-jlr200

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    Caligiuri G., Nicoletti A., Poirier B., Hansson G.K. Protective Immunity against Atherosclerosis Carried by B Cells of Hypercholesterolemic Mice. J. Clin. Investig. 2002;109:745-753.

    Not in our library10.1172/jci7272

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    Major A.S., Fazio S., Linton M.F. B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor-Null Mice. Arterioscler. Thromb. Vasc. Biol. 2002;22:1892-1898.

    Not in our library10.1161/01.atv.0000039169.47943.ee

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    Shaw P.X., Horkko S., Chang M.K., Curtiss L.K., Palinski W., Silverman G.J., Witztum J.L. Natural Antibodies with the T15 Idiotype May Act in Atherosclerosis, Apoptotic Clearance, and Protective Immunity. J. Clin. Investig. 2000;105:1731-1740.

    Not in our library10.1172/jci8472

  138. 138.

    Schulz C., Massberg S. Platelets in Atherosclerosis and Thrombosis. Handb. Exp. Pharmacol. 2012;111-133.

    Not in our library10.1007/978-3-642-29423-5_5

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    Lievens D., von Hundelshausen P. Platelets in Atherosclerosis. Thromb. Haemost. 2011;106:827-838.

    Not in our library10.1160/th11-08-0592

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    Huo Y., Ley K.F. Role of Platelets in the Development of Atherosclerosis. Trends Cardiovasc. Med. 2004;14:18-22.

    Not in our library10.1016/j.tcm.2003.09.007

  141. 141.

    Badimon L., Padró T., Vilahur G. Atherosclerosis, Platelets and Thrombosis in Acute Ischaemic Heart Disease. Eur. Heart J. Acute Cardiovasc. Care. 2012;1:60-74.

    Not in our library10.1177/2048872612441582

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    Koltai K., Kesmarky G., Feher G., Tibold A., Toth K. Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications. Int. J. Mol. Sci. 2017;18:1803.

    Not in our library10.3390/ijms18081803

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    Andrews R.K., Berndt M.C. Platelet Physiology and Thrombosis. Thromb. Res. 2004;114:447-453.

    Not in our library10.1016/j.thromres.2004.07.020

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    Ruggeri Z.M., Bader R., de Marco L. Glanzmann Thrombasthenia: Deficient Binding of Von Willebrand Factor to Thrombin-Stimulated Platelets. Proc. Natl. Acad. Sci. USA. 1982;79:6038-6041.

    Not in our library10.1073/pnas.79.19.6038

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    Ni H., Denis C.V., Subbarao S., Degen J.L., Sato T.N., Hynes R.O., Wagner D.D. Persistence of Platelet Thrombus Formation in Arterioles of Mice Lacking Both Von Willebrand Factor and Fibrinogen. J. Clin. Investig. 2000;106:385-392.

    Not in our library10.1172/jci9896

  146. 146.

    Hantgan R.R. Fibrin Protofibril and Fibrinogen Binding to ADP-Stimulated Platelets: Evidence for a Common Mechanism. Biochim. Biophys. Acta. 1988;968:24-35.

    Not in our library10.1016/0167-4889(88)90040-7

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    Bennett J.S., Vilaire G. Exposure of Platelet Fibrinogen Receptors by ADP and Epinephrine. J. Clin. Investig. 1979;64:1393-1401.

    Not in our library10.1172/jci109597

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    Das U.N. Atherosclerosis and Prostaglandins. Int. J. Tissue React. 1982;4:127-132.

    Not in our library

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    Martínez-Sánchez S.M., Minguela A., Prieto-Merino D., Zafrilla-Rentero M.P., Abellán-Alemán J., Montoro-García S. The Effect of Regular Intake of Dry-Cured Ham Rich in Bioactive Peptides on Inflammation, Platelet and Monocyte Activation Markers in Humans. Nutrients. 2017;9:321.

    Not in our library10.3390/nu9040321

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    Molica F., Stierlin F.B., Fontana P., Kwak B.R. Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function. Int. J. Mol. Sci. 2017;18:850.

    Not in our library10.3390/ijms18040850

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    Virmani R., Burke A.P., Farb A. Plaque Rupture and Plaque Erosion. Thromb. Haemost. 1999;82:1-3.

    Not in our library

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    Lafont A. Basic Aspects of Plaque Vulnerability. Heart. 2003;89:1262-1267.

    Not in our library10.1136/heart.89.10.1262

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    Hansson G.K., Libby P., Tabas I. Inflammation and Plaque Vulnerability. J. Int. Med. 2015;278:483-493.

    Not in our library10.1111/joim.12406

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    Shah P.K. Mechanisms of Plaque Vulnerability and Rupture. J. Am. Coll. Cardiol. 2003;41:S15-S22.

    Not in our library10.1016/s0735-1097(02)02834-6

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