Response In Atherosclerosis Research Articles

T cells in atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis. Among CD4⁺T cells, T(h)1 cells are pro-atherogenic, T(reg) cells are athero-protective and the role of T(h)2 and T(h)17 cells remains unclear. The role of follicular helper T cells in atherosclerosis remains unknown, as is the role of CD8⁺T cells. NKT cells bind glycolipid antigens and exert a pro-atherogenic role. The antigen specificity of T-cell responses in atherosclerosis is poorly understood. In order to enable antigen-specific prevention or therapy, a better understanding of these mechanisms is needed.

Macrophage PPAR gamma Co‐activator‐1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid

Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo. PGC-1α was identified as a hub gene within a cluster in the aorta of the apoE−/− mouse in the CLA-induced regression model. PGC-1α was localized to macrophage/foam cells in the murine aorta where its expression was increased during CLA-induced regression. PGC-1α expression was also detected in macrophages in human atherosclerosis and was inversely linked to disease progression in patients with the disease. Deletion of PGC-1α in bone marrow derived macrophages promoted, whilst over expression of the gene inhibited foam cell formation. Importantly, macrophage specific deletion of PGC-1α accelerated atherosclerosis in the LDLR−/− mouse in vivo. These novel data support a functional role for PGC-1α in atheroprotection.

Atorvastatin Inhibits the 5-Lipoxygenase Pathway and Expression of CCL3 to Alleviate Atherosclerotic Lesions in Atherosclerotic ApoE Knockout Mice

The 5-lipoxygenase (5-LO) pathway and the chemokine CCL3 are involved in the inflammatory processes of atherosclerosis. Statins have shown cholesterol-independent pleiotropic effects on antiimmune and antiinflammatory responses in atherosclerosis. We postulated that this effect may be associated with the 5-LO pathway and CCL3. ApoE knockout mice were randomized into control group (normal diet), atherosclerosis group (high-cholesterol diet), and atorvastatin group (high-cholesterol diet and atorvastatin). Sixteen weeks later, aortic roots were stained with hematoxylin and eosin. Total cholesterol and low-density lipoprotein cholesterol were measured by the enzymatic methods. The gene and protein expressions of 5-LO and CCL3 were detected separately through real-time reverse transcription polymerase chain reaction and western blotting analyses. The serum levels of leukotriene B4 and leukotriene D4 were measured by enzyme-linked immunosorbent assay. All mice have atherosclerotic plaques, mice in the control group have only tiny atherosclerotic plaques, but mice in the atherosclerosis group and atorvastatin group have typical atherosclerotic plaques. The corrected plaque areas (plaque area/luminal area) of the aortas of mice in the atorvastatin group were significantly decreased compared with those of the atherosclerosis group. The serum cholesterol levels of the atorvastatin group were not of significant difference compared with those of the atherosclerosis group. The gene and protein expressions of 5-LO and CCL3 in the aortas, as well as the serum levels of leukotriene B4 and leukotriene D4 in atorvastatin group, were markedly reduced compared with those of the atherosclerosis group. These data suggested that atorvastatin significantly alleviated atherosclerotic lesions by inhibiting the 5-LO pathway and down regulating the expression of CCL3 in ApoE-/- mice.

Major Vault Protein Regulates Class A Scavenger Receptor-mediated Tumor Necrosis Factor-α Synthesis and Apoptosis in Macrophages

Atherosclerosis is considered a disease of chronic inflammation largely initiated and perpetuated by macrophage-dependent synthesis and release of pro-inflammatory mediators. Class A scavenger receptor (SR-A) expressed on macrophages plays a key role in this process. However, how SR-A-mediated pro-inflammatory response is modulated in macrophages remains ill defined. Here through immunoprecipitation coupled with mass spectrometry, we reported major vault protein (MVP) as a novel binding partner for SR-A. The interaction between SR-A and MVP was confirmed by immunofluorescence staining and chemical cross-linking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-α production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-α synthesis in macrophages via the caveolin- instead of clathrin-mediated endocytic pathway linked to p38 and JNK, but not ERK, signaling pathways. Importantly, fucoidan invoked an enrichment of MVP in lipid raft, a caveolin-reliant membrane structure, and enhanced the interaction among SR-A, caveolin, and MVP. Finally, we demonstrated that MVP elimination ameliorated SR-A-mediated apoptosis in macrophages. As such, MVP may fine-tune SR-A activity in macrophages which contributes to the development of atherosclerosis.

Human neutrophil peptides induce inflammatory atherosclerotic events (P5115)

Abstract Atherosclerosis includes complex inflammatory events that leafs to leukocyte recruitment, adhesion and migration, foam cell formation, and platelet aggregation. Human neutrophil peptides (HNP), the major protein content in the azurophilic granules, are released upon PMN activation, and have been found in the lesion area of coronary artery diseases. We hypothesized that HNP play an important role in PMN-mediated inflammatory cardiovascular responses in atherosclerosis. Human coronary artery endothelial cells were stimulated with HNP at a clinical relevant concentration for 4 h and 8 h, followed by cocultured with human peripheral monocyters for 2 h. The monocyte adhesion to the endothelial cells and transmigration increased in the HNP-treated conditions than in the controls. Stimulation of human monocyte-derived macrophages with HNP resulted in oxidative stress that accelerated foam cell formation, which was attenuated by the administration of superoxide dismutase. Stimulation of platelets with HNP resulted in platelet aggregation and deletion of LDL receptor-related protein8 (LRP8), the only LRP phenotype expressed in platelets had no response to HNP. The HNP-induced production of reelin, a LRP8 ligand, by the arterial endothelial cells was required for platelet aggregation. In conclusion, HNP exert pro-atherosclerotic properties mediated through reelin-LRP8 signaling pathways.

Assessment of cerebral oxygenation oscillations in subjects with hypertension

PurposeThe objective of this study was to assess the spontaneous oscillations in subjects with hypertension based on the wavelet transform of cerebral oxygenation signal measured with near-infrared spectroscopy (NIRS). MethodsContinuous recordings of NIRS and arterial blood pressure (ABP) signals were obtained from simultaneous measurements in 20 healthy subjects (age: 70.8±5.2years) and 22 subjects with hypertension (age: 72.5±6.8years). ResultsUsing spectral analysis based on wavelet transform, five frequency intervals were identified (I, 0.4–2Hz; II, 0.15–0.4Hz; III, 0.06–0.15Hz; IV, 0.02–0.06Hz and V, 0.005–0.02Hz). The amplitudes of Δ[Hb] and Δ[HbO2] in intervals I, II and III were significantly higher in hypertensive patients, who have increased mean flow velocity in middle cerebral artery (MCA), compared to that in the healthy subjects (p<0.01). The amplitudes of the ABP in frequency intervals III and V were significantly higher in hypertensive patients than in the healthy subjects (p<0.01). ConclusionsThe present findings revealed that hypertension and increased mean flow velocity in MCA have significant effect on the cerebral oscillations. The higher cerebral oscillations might be related to the intracerebral atherosclerosis in response to systemic hypertension. In addition, the higher spontaneous oscillations in intervals III and V in ABP indicate a metabolic regulation and myogenic response to hypertension.

Atherosclerosis

DOI:10.1097/MOL.0b013e32835ec608 Atherosclerosis is a chronic inflammatory reaction of the arterial wall characterized by the infiltration of inflammatory cells into the nascent atherosclerotic lesions leading to its growth and eventual destabilization [1,2]. Transforming growth factor beta (TGFb), an anti-inflammatory cytokine, is centrally involved in balancing the immune response in atherosclerosis [3–5]. Recently, Lievens et al. [6 && ] reported that abrogation of TGFb signaling in dendritic cells leads to a two-fold increase in lesion size and acceleration of plaque inflammation. Furthermore, this overexpression of dominant-inactive TGFb receptor in CD11cþ cells increased cytokine production and T-cell content in the plaque. In vitro, dendritic cells deficient in TGFb signaling displayed a profound inflammatory phenotype promoting T-cell activation, proliferation, and differentiation into effector cells, thus providing a mechanistic link to the changes observed in the vasculature. Taken together, this study suggests a potential therapeutic approach in which dendritic cell-specific promotion of TGF signaling may dampen atherosclerosis without the detrimental profibrotic and neoplastic complications caused by systemic TGFR activation. Regulatory T cells (Tregs) are increasingly recognized as potent atheroprotective players [7]. Interestingly, TGFb plays a dual role in Tregs, as it regulates their differentiation and function but also is secreted as one of the most potent effector cytokines. Treg numbers and function were modulated in the atherosclerosis models either by direct adoptive transfer or by indirect measures such as vaccination [8]. Treg function is also mediated by indoleamine 2,3-dioxygenase (IDO) and IDOcatalyzed tryptophan metabolism [9]. The tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) inhibits inflammation in different experimental autoimmune disease models by repressing proinflammatory T cells and increasing the percentage of Tregs [10]. Zhang et al. [11 && ] now show that 3-HAA reduced atherosclerotic lesion formation in hyperlipidemic mice. Interestingly, 3-HAA

Lack of association between a functional variant of the BRCA-1 related associated protein (BRAP) gene and ischemic stroke

BackgroundAtherosclerosis shares common pathogenic features with myocardial infarction (MI) and ischemic stroke. BRCA-1 associated protein (BRAP), a newly identified risk gene for MI, aggravates the inflammatory response in atherosclerosis. The aim of this study was to test the association between the BRAP gene and stroke in a Taiwanese population.MethodsA total of 1,074 stroke patients and 1,936 controls were genotyped for the functional SNP rs11066001. In our previous studies, the rare allele of this SNP has been repeatedly shown to exert a recessive effect. Therefore, in the current study, we tested for the same recessive model. First, the genotype distributions between all the controls and all the stroke cases were compared. Then to reduce heterogeneity, we explored several population subsets by selecting young stroke subjects (using 45 years of age as the cutoff point), age- and sex-comparable controls, plaque-free controls, and stroke subtypes.ResultsWe did not find any significant association for the entire data set (OR = 0.94, p = 0.74) or for the subset analyses using age- and sex-comparable controls (p = 0.70) and plaque-free controls (p = 0.91). Analyses of the four stroke subtypes also failed to show any significant associations (p = 0.42 – 0.98). For both young and old subjects, the GG genotype of rs11066001 was similar in the stroke cases and unmatched controls (8.1% vs. 9.4% in young subjects and 8.0% vs. 7.8% in old subjects). Comparing stroke cases with plaque-free controls also failed to find any significant association.ConclusionsThe BRAP polymorphism may not play an important role in ischemic stroke in the studied population.

Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis

Our studies in HUVECs show that ox-LDL induced autophagy and damaged mtDNA leading to TLR9 expression. LOX-1 antibody or the ROS inhibitor apocynin attenuated ox-LDL-mediated autophagy, mtDNA damage and TLR9 expression, suggesting that these events are LOX-1 and ROS-dependent phenomena. Experiments using siRNA to DNase II indicated that DNase II digests mtDNA to protect the tissue from inflammation. Next, we studied and found intense autophagy, TLR9 expression and inflammatory signals (CD45 and CD68) in the aortas of LDLR knockout mice fed high cholesterol diet. Deletion of LOX-1 (LDLR/LOX-1 double knockout mice) attenuated autophagy, TLR9 expression as well as CD45 and CD68. Damaged mtDNA signal was also very high in LDLR knockout mice aortas, and this signal was attenuated by LOX-1 deletion. Thus, it appears that oxidative stress-mediated damaged mtDNA that escapes autophagy induces a potent inflammatory response in atherosclerosis.

Pathogenic Role of Modified LDL Antibodies and Immune Complexes in Atherosclerosis

There is strong evidence supporting a key role of the adaptive immune response in atherosclerosis, given that both activated Th cells producing predominantly interferon-γ and oxidized LDL (oxLDL) and the corresponding antibodies have been isolated from atheromatous plaques. Studies carried out using immune complexes (IC) prepared with human LDL and rabbit antibodies have demonstrated proatherogenic and pro-inflammatory properties, mostly dependent on the engagement of Fcγ receptors Ⅰ and Ⅱ in macrophages and macrophage-like cell lines. Following the development of a methodology for isolating modified LDL (mLDL) antibodies from serum and isolated IC, it was confirmed that antibodies reacting with oxLDL and advanced glycation end product-modified LDL are predominantly IgG of subtypes 1 and 3 and that mLDL IC prepared with human reagents possesses pro-inflammatory and proatherogenic properties. In previous studies, LDL separated from isolated IC has been analyzed for its modifications, and the reactivity of antibodies isolated from the same IC with different LDL modifications has been tested. Recently, we obtained strong evidence suggesting that the effects of mLDL IC on phagocytic cells are modulated by the composition of the mLDL. Clinical studies have shown that the level of mLDL in circulating IC is a strong predictor of cardiovascular disease (CVD) and, in diabetic patients, other significant complications, such as nephropathy and retinopathy. In conclusion, there is convincing ex vivo and clinical data supporting the hypothesis that, in humans, the humoral immune response to mLDL is pathogenic rather than protective.

Effects of Black Soybean on Atherogenic Prevention in Hypercholesterolemic Rabbits and on Adhesion Molecular Expression in Cultured HAECs

The aim of the study was to investigate the effect of black soybean (BS) on the susceptibility of low-density lipoprotein (LDL) in hypercholesterolemic New Zealand white rabbits. Effects of the BS extract (BSE) and its components on monocyte adhesion of human aortic endothelial cells (HAECs), and adhesion molecule were investigated. Rabbits were divided into four groups, including control, 0.5% cholesterol with 20% casein (either with or without 0.5% vitamin E), and BS groups, all fed for 8 weeks. LDL was treated with 10 μM Cu2+ in vitro to determine the LDL lag time, and the vitamin E content of LDL was determined. The thickness of the tunica intima was measured on paraffin sections of thoracic aortas and aortic arches stained with Movat’s pentachrome. HAECs were pretreated with 100 μg/ml of BSE, and 10 μM of genistein, daidzein, cyanidin, and aspirin for 18 h, followed by tumor necrosis factor (TNF)-α (2 ng/ml) for 6 h, after which U937 cell adhesion was determined. Adhesion molecule expression was examined using ELISAs. The LDL lag time in the BS group was similar to that in the vitamin E group, while its lag time was significantly longer than those in the control and casein groups. The ratio of the intimal area/medial area of the aortic arch of the casein group was significantly higher than those in the control, BS, and vitamin E groups. The vitamin E group had the lowest value, and was closest to the control group. The BS group exhibited a significantly decreased atheroma region in the aortic arch compared to the casein group. Pre-incubation with BSE, genistein, daidzein, cyanidin, and aspirin significantly decreased adhesion by U937 monocytic cells to TNF-α stimulated HAECs. Genistein, daidzein, cyanidin, and aspirin significantly suppressed the expression of vascular cell adhesion molecule (VCAM)-1. Only genistein and aspirin significantly decreased intracellular adhesion molecule (ICAM)-1 expression compared to TNF-α treatment, while no treatments had any effect on E-selectin expression. BS significantly prolonged the LDL lag time and decreased the atheroma region of the aortic arch in hypercholesterolemic rabbits, thereby exerting an antiatherosclerotic effect. Presumably, the BSE downregulate intracellular redox-dependent signaling pathways in HAECs upon TNF-α stimulation through regulating NF-κB, thereby attenuating the inflammatory response in atherosclerosis. The antiatherogenic and anti-inflammatory effects of BS can be used as a nutraceutical for atherogenesis prevention.

Abstract 9943: Aged Garlic Extract Plus Coenzyme Q10 Significantly Reduce Perceived Mental Stress, Inflammaion and Subclinical Atherosclerosis in Firefighters ‰the FAITH Randomized Clinical Trial

Background: We previously reported that Aged Garlic Extract (AGE) is associated with significant reduction of subclinical atherosclerosis measured by coronary artery calcium (CAC) in asymptomatic individuals. Stressful lifestyle is a well-known risk factor of atherosclerosis. In the current study, we evaluate the effect of AGE plus CoQ10 on perceived mental stress score (PMSS), inflammation and CAC in Firefighters with highly stressful lifestyle. Methods: In this placebo-controlled, double blinded, randomized trial, 65 firefighters, age 55±6 years, 100% male, with intermediate risk for coronary artery disease (CAD) subjects were randomized to AGE and CoQ10 vs. placebo for 1-year. Subjects’ mental stress was assessed as perceived mental stress score (PMSS) using validated perceived mental stress questionnaire (PSQ). PMSS, high sensitive C reactive protein (CRP) and CAC were measured at baseline and follow up. Results: There was no significant difference between PMSS, CRP, CAC and other risk factors at baseline (p&gt;0.5). At-year follow-up, PMSS reduction was significantly higher in AGE plus CoQ10 as compared to placebo (-10.6% vs. 14.7%, p=0.001). After adjustment for risk factors, AGE plus CoQ10 was independently associated with significant reduction in PMSS, CRP and CAC (p&lt;0.05) (Table). In which, the likelihood of decrease in PMSS was 84% higher with AGE plus CoQ10. Decrease in PMSS in response to AGE plus CoQ10 was significantly associated with decrease in CRP and CAC (p&lt;0.05). Conclusion: This study reported the beneficial effect of AGE-CoQ10 on mental stress in subjects with highly stressful lifestyle independent of risk factors. Furthermore, it highlights the association between decrease in mental stress , inflammation and atherosclerosis in response to such therapy.

MicroRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos

Oxidized LDL (ox-LDL) activates dendritic cells (DCs), thereby initiating inflammation responses in atherosclerosis, yet the modulatory mechanisms remain unclear. MicroRNAs (miRNAs) are important regulators for DC functions. This study evaluated the regulation by miRNAs of the ox-LDL-induced DC immune response. In CD11c+ DCs from ApoE-deficient mice with hyperlipidemia, microRNA miR-181a was significantly up-regulated. In cultured bone marrow-derived DCs (BMDCs), ox-LDL promoted DC maturation and up-regulated miR-181a expression. Abundance of miR-181a attenuated ox-LDL-induced CD83 and CD40 expression, inhibited the secretion of interleukin (IL)-6 and TNF-α, and up-regulated IL-10, an important anti-inflammatory cytokine that was inhibited by ox-LDL. Inhibition of the endogenous miR-181a reversed the effects on CD83 and CD40 as well as the effects on IL-6 and TNF-α. The putative target genes of miR-181a were evaluated by gene ontology assessment, and the c-Fos-mediated inflammation pathway was identified. miR-181a targeted the 3′ untranslated region of c-Fos mRNA by luciferase experiments. Thus, abundance of miR-181a reduced c-Fos protein, whereas inhibition of miR-181a increased c-Fos protein in BMDCs. We therefore suggest that miR-181a attenuates ox-LDL-stimulated immune inflammation responses by targeting c-Fos in DCs.

Inhibition of the transcription factor c-Jun by the MAPK family, and not the NF-κB pathway, suggests that peanut extract has anti-inflammatory properties

BackgroundTumor necrosis factor-α (TNF-α) is involved in inflammatory responses in atherosclerosis. We propose an in vitro cellular assay to evaluate the anti-inflammatory mechanisms of potential modifiers such as food extracts. In the current model we assessed an anti-inflammatory effect of polyphenol-rich peanut extract in lipopolysaccharide (LPS)-induced THP-1 monocytes. MethodsTHP-1 monocytes were incubated with peanut extract (5, 25, 50 and 100μg/mL) consisting of 39% flavonols, 37% flavanols and 24% phenolic acid (or BAY 11-7082 (5μM) as experiment control) for 1h and then stimulated with LPS (500ng/mL) for 4h. Cytotoxicity was measured as lactate dehydrogenase (LDH) activity release. NF-κB and MAPK family were determined by TransAm kit while TNF-α mRNA levels and its mRNA stability by RT-PCR. Intra- and extracellular TNF-α protein was measured by ELISA, and TNF-α converting enzyme (TACE) activity by a fluorimetric assay. ResultsPeanut extract inhibited the maximal LPS-induced extracellular TNF-α protein secretion by 18%, 29% and 47% at 25, 50 and 100μg/mL, respectively (P<0.05). LPS stimulation revealed that 85% of TNF-α was released extracellularly while 15% remained intracellular. Peanut extract did not modify NF-κB but, instead, reduced c-Jun transcription factor activity (P<0.05), decreased TNF-α mRNA (albeit non-significantly) and had no effect on mRNA stability and TACE activity. ConclusionPolyphenol-rich peanut extract reduces extracellular TNF-α protein by inhibiting c-Jun transcription factor from MAPK family, suggesting an anti-inflammatory effect. The proposed THP-1 monocyte model could be used to assess food extract impact (site and size effects) on the inflammation pathway.

Diet intervention reduces uptake of αvβ3 integrin-targeted PET tracer 18F-galacto-RGD in mouse atherosclerotic plaques

BackgroundExpression of αvβ3 integrin has been proposed as a marker for atherosclerotic lesion inflammation. We studied whether diet intervention reduces uptake of αvβ3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD in mouse atherosclerotic plaques. Methods and ResultsHypercholesterolemic LDLR−/− ApoB100/100 mice on high-fat diet for 4 months were randomized to further 3 months on high-fat diet (high-fat group, n = 8) or regular mouse chow (intervention group, n = 7). Intima-media ratio describing plaque burden was comparable between intervention and high-fat groups (2.0 ± 0.5 vs 2.3 ± 0.8, P = .5). Uptake of 18F-galacto-RGD in the aorta was lower in the intervention than high-fat group (%ID/g 0.16 vs 0.23, P < .01). Autoradiography showed 35% lower uptake of 18F-galacto-RGD in the atherosclerotic plaques in the intervention than high-fat group (P = .007). Uptake of 18F-galacto-RGD in plaques correlated with uptake of 3H-deoxyglucose and nuclear density, which was lower in the intervention than high-fat group (P = .01). Flow cytometry demonstrated macrophages expressing αv and β3 integrins in the aorta. ConclusionsUptake of 18F-galacto-RGD in mouse atherosclerotic lesions was reduced by lipid-lowering diet intervention. Expression of αvβ3 integrin is a potential target for evaluation of therapy response in atherosclerosis.

Lymphocytes and the Adventitial Immune Response in Atherosclerosis

Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.

Distinct MAPK pathways are involved in IL-23 production in dendritic cells cocultured with NK cells in the absence or presence of angiotensin II

Accumulated evidence suggests that the crosstalk between dendritic cells (DCs) and natural killer (NK) cells enhances each other's capacity, and results in the production of a variety of soluble factors. However, little is known about the effect of DC–NK crosstalk in interleukin-23 (IL-23) production. In the present study we show that DC–NK coculture caused a high expression of IL-23, angiotensin II (Ang II) alone moderately increased IL-23 production in DCs, but decreased IL-23 secretion in the DC–NK coculture system. We found that Ang II does not influence DC maturation in DC–NK crosstalk. We next investigated the mitogen-activated protein kinase (MAPK) pathway in DCs. We found that Ang II increased IL-23 production through the extracellular signal-related kinase (ERK) pathway. All three MAPK members c-Jun N-terminal kinase (JNK), ERK and p38 were involved in IL-23 production in the DC–NK coculture system. In the presence of Ang II, only the JNK pathway seems to play a role in IL-23 production in DCs cocultured with NK. These data suggest that distinct MAPK pathways are involved in IL-23 production in DCs in response to different stimuli. This work demonstrates for the first time that IL-23 is produced in the DC–NK coculture system, and that Ang II is involved in DC–NK crosstalk. This data will act as a resource that allows further exploitation of role of immune response in atherosclerosis.

MicroRNAs in the regulation of immune cell functions – implications for atherosclerotic vascular disease

Regarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis.

Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

Tertiary lymphoid organs (TLOs) emerge in tissues in response to non-resolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE−/− mice. ATLOs are structured into T cell areas harboring conventional dendritic cells and monocyte-derived DCs; B cell follicles containing follicular dendritic cells within activated germinal centers; and peripheral niches of plasma cells. ATLOs also show extensive neoangiogenesis, aberrant lymphangiogenesis, and high endothelial venule (HEV) neogenesis. Newly formed conduit networks connect the external lamina of the artery with HEVs in T cell areas. ATLOs recruit and generate lymphocyte subsets with opposing activities including activated CD4+ and CD8+ effector T cells, natural and induced CD4+ T regulatory (nTregs; iTregs) cells as well as B-1 and B-2 cells at different stages of differentiation. These data indicate that ATLOs organize dichotomic innate and adaptive immune responses in atherosclerosis. In this review we discuss the novel concept that dichotomic immune responses toward atherosclerosis-specific antigens are carried out by ATLOs in the adventitia of the arterial wall and that malfunction of the tolerogenic arm of ATLO immunity triggers transition from silent autoimmune reactivity to clinically overt disease.

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta

Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells (DCs) are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and DC precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and DCs. Recent data suggest that several populations of macrophages and DCs can co-exist within the aorta. Although the functions of M1, M2, Mox, and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic DCs provide novel insights into the biology of aortic DC subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of DCs and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.