Publications by authors named "Claudia Monaco"

103 Publications

CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis.

Circ Res 2021 May 12. Epub 2021 May 12.

Kennedy Institue of Rheumatology, University of Oxford, UNITED KINGDOM.

Inflammation is a basic component of the pathogenesis of atherosclerosis. CD200 is an immune checkpoint known to control macrophage activation. CD200 recently emerged in the Framingham Heart Study and 2 other cohorts as being potentially relevant in CVD. The role of this pathway in CVD is unknown. We sought to examine the role of CD200 in atherosclerosis. Using hypercholesterolemic ApoE-/- mice, we demonstrate that whole-body CD200 deficiency augments atherosclerotic lesion formation and vulnerability. Administration of a CD200-Fusion protein reduces neointima formation. Our data show that the CD200-CD200R pathway restrains activation of CD200R+ lesional macrophages, their production of CCR2 ligands, and monocyte recruitment in vitro and in vivo in an air pouch model. Loss of CD200 leads to an excessive accumulation of classical Ly6Chi monocytes and CCR2+ macrophages within the atherosclerotic aorta, as assessed by mass cytometry. Moreover, we uncover a previously uncharacterised effect of the CD200/CD200R pathway in limiting dysregulated monopoiesis and Ly6Chi monocytosis in hypercholesterolemic mice. Bone marrow chimera experiments demonstrate that the CD200-CD20R pathway enables two complementary and tissue-dependent strategies to limit atherogenesis: CD200 expression by bone-marrow derived cells limits systemic monocytosis, while CD200 expression by non-haematopoietic cells, e.g. endothelial cells, prevents local plaque growth. We show that CD200R signalling controls monopoiesis and macrophage activation through inhibiting phosphorylation of STAT1. Finally, CD200R expression on classical monocytes in peripheral blood of patients with coronary artery disease (CAD) is associated with a lower burden of CAD and a more favourable Virtual Histology plaque profile. The CD200 checkpoint is a key limiting factor for monopoiesis, monocyte-macrophage activation and recruitment in atherosclerosis with conserved features in human and mouse. It thus offers a novel potential therapeutic pathway to treat CVD.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316062DOI Listing
May 2021

COVID-19 and myocarditis: a systematic review and overview of current challenges.

Heart Fail Rev 2021 Mar 24. Epub 2021 Mar 24.

Royal Brompton Hospital, Imperial College London, London, UK.

Myocardial inflammation in COVID-19 has been documented. Its pathogenesis is not fully elucidated, but the two main theories foresee a direct role of ACE2 receptor and a hyperimmune response, which may also lead to isolated presentation of COVID-19-mediated myocarditis. The frequency and prognostic impact of COVID-19-mediated myocarditis is unknown. This review aims to summarise current evidence on this topic. We performed a systematic review of MEDLINE and Cochrane Library (1/12/19-30/09/20). We also searched clinicaltrials.gov for unpublished studies testing therapies with potential implication for COVID-19-mediated cardiovascular complication. Eligible studies had laboratory confirmed COVID-19 and a clinical and/or histological diagnosis of myocarditis by ESC or WHO/ISFC criteria. Reports of 38 cases were included (26 male patients, 24 aged < 50 years). The first histologically proven case was a virus-negative lymphocytic myocarditis; however, biopsy evidence of myocarditis secondary to SARS-CoV-2 cardiotropism has been recently demonstrated. Histological data was found in 12 cases (8 EMB and 4 autopsies) and CMR was the main imaging modality to confirm a diagnosis of myocarditis (25 patients). There was a substantial variability in biventricular systolic function during the acute episode and in therapeutic regimen used. Five patients died in hospital. Cause-effect relationship between SARS-CoV-2 infection and myocarditis is difficult to demonstrate. However, current evidence demonstrates myocardial inflammation with or without direct cardiomyocyte damage, suggesting different pathophysiology mechanisms responsible of COVID-mediated myocarditis. Established clinical approaches should be pursued until future evidence support different actions. Large multicentre registries are advisable to elucidate further.
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http://dx.doi.org/10.1007/s10741-021-10087-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988375PMC
March 2021

Does a myocardial infarction boost your (B cell) memory?

Eur Heart J 2021 Mar;42(9):948-950

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford.

Graphical abstract Establishment of an autoreactive B cell memory after myocardial infarction: a working hypothesis. The demise of cardiac cells leads to the release of cryptoantigens that induce a humoral immune response that leads to accumulation of immunoglobulins in plaques and eventually amplifies atherogenesis at remote sites.
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http://dx.doi.org/10.1093/eurheartj/ehaa1059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936513PMC
March 2021

The Potential for Repurposing Anti-TNF as a Therapy for the Treatment of COVID-19.

Med (N Y) 2020 Dec 3;1(1):90-102. Epub 2020 Dec 3.

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.

Coronavirus disease 2019 (COVID-19) currently has few effective treatments. Given the uncertainty surrounding the effectiveness and uptake of a vaccine, it is important that the search for treatments continue. An exaggerated inflammatory state is likely responsible for much of the morbidity and mortality in COVID-19. Elevated levels of tumor necrosis factor (TNF), a key pro-inflammatory cytokine, have been shown to be associated with increased COVID-19 mortality. In patients with rheumatoid arthritis, TNF blockade reduces not only biologically active TNF but other pro-inflammatory cytokines important in COVID-19 hyperinflammation. Observational data from patients already on anti-TNF therapy show a reduced rate of COVID-19 poor outcomes and death compared with other immune-suppressing therapies. Anti-TNF has a long history of safe use, including in special at-risk populations, and is widely available. The case to adequately assess anti-TNF as a treatment for COVID-19 is compelling.
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http://dx.doi.org/10.1016/j.medj.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713589PMC
December 2020

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Kennedy Institute of Rheumatology and.

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.
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http://dx.doi.org/10.1172/jci.insight.139163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605529PMC
October 2020

Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans.

Eur Heart J 2020 08;41(31):2938-2948

Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Aims: GITR-a co-stimulatory immune checkpoint protein-is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD).

Methods And Results: GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr-/-Apoe-/- mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr-/-Apoe-/- monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity.

Conclusion: Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.
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http://dx.doi.org/10.1093/eurheartj/ehaa484DOI Listing
August 2020

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

Circ Res 2020 07 16;127(3):402-426. Epub 2020 Jul 16.

La Jolla Institute for Immunology, CA (C.C.H., Y.G., H.Q.D., K.L.).

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371244PMC
July 2020

Structure-preserving visualisation of high dimensional single-cell datasets.

Sci Rep 2019 06 20;9(1):8914. Epub 2019 Jun 20.

Bering Limited, London, United Kingdom.

Single-cell technologies offer an unprecedented opportunity to effectively characterize cellular heterogeneity in health and disease. Nevertheless, visualisation and interpretation of these multi-dimensional datasets remains a challenge. We present a novel framework, ivis, for dimensionality reduction of single-cell expression data. ivis utilizes a siamese neural network architecture that is trained using a novel triplet loss function. Results on simulated and real datasets demonstrate that ivis preserves global data structures in a low-dimensional space, adds new data points to existing embeddings using a parametric mapping function, and scales linearly to hundreds of thousands of cells. ivis is made publicly available through Python and R interfaces on https://github.com/beringresearch/ivis .
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http://dx.doi.org/10.1038/s41598-019-45301-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586841PMC
June 2019

The aorta can act as a site of naïve CD4+ T-cell priming.

Cardiovasc Res 2020 02;116(2):306-316

Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK.

Aims: Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood.

Methods And Results: Here, we have identified naïve T cells in the aorta of wild-type and T-cell receptor transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 receptor. In experimental atherosclerosis the aorta supports CD4+ T-cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion.

Conclusion: Our results demonstrate that the aorta can support T-cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression.
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http://dx.doi.org/10.1093/cvr/cvz102DOI Listing
February 2020

Identifying the anti-inflammatory response to lipid lowering therapy: a position paper from the working group on atherosclerosis and vascular biology of the European Society of Cardiology.

Cardiovasc Res 2019 01;115(1):10-19

Karolinska Institutet, Stockholm, Sweden.

Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy.
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http://dx.doi.org/10.1093/cvr/cvy293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302260PMC
January 2019

Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension.

Am J Respir Crit Care Med 2019 01;199(2):199-210

1 Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection.

Objectives: To study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models.

Methods: Lung tissue and endothelial cells from patients with PAH were investigated by polymerase chain reaction, immunofluorescence, and apoptosis assays. TLR3 and TLR3 mice were exposed to chronic hypoxia and SU5416. Chronic hypoxia or chronic hypoxia/SU5416 rats were treated with the TLR3 agonist polyinosinic/polycytidylic acid (Poly[I:C]).

Measurements And Main Results: TLR3 expression was reduced in PAH patient lung tissue and endothelial cells, and TLR3 mice exhibited more severe pulmonary hypertension following exposure to chronic hypoxia/SU5416. TLR3 knockdown promoted double-stranded RNA signaling via other intracellular RNA receptors in endothelial cells. This was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via IL-10 in rat endothelial cells. In vivo, high-dose Poly(I:C) reduced pulmonary hypertension in both rat models in proof-of-principle experiments. In addition, Poly(I:C) also reduced right ventricular failure in established pulmonary hypertension.

Conclusions: Our work identifies a novel role for TLR3 in PAH based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis and pulmonary vascular remodeling.
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http://dx.doi.org/10.1164/rccm.201707-1370OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353001PMC
January 2019

Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages.

Front Immunol 2018 20;9:1419. Epub 2018 Jun 20.

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H)-dione (6--octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84 cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases.
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http://dx.doi.org/10.3389/fimmu.2018.01419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019444PMC
June 2018

Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice.

Eur J Prev Cardiol 2018 06 14;25(9):948-955. Epub 2018 May 14.

16 University Medical Centre Utrecht, Netherlands.

Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.
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http://dx.doi.org/10.1177/2047487318773384DOI Listing
June 2018

Immune cell census in murine atherosclerosis: cytometry by time of flight illuminates vascular myeloid cell diversity.

Cardiovasc Res 2018 08;114(10):1360-1371

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, UK.

Aims: Atherosclerosis is characterized by the abundant infiltration of myeloid cells starting at early stages of disease. Myeloid cells are key players in vascular immunity during atherogenesis. However, the subsets of vascular myeloid cells have eluded resolution due to shared marker expression and atypical heterogeneity in vascular tissues. We applied the high-dimensionality of mass cytometry to the study of myeloid cell subsets in atherosclerosis.

Methods And Results: Apolipoprotein E-deficient (ApoE-/-) mice were fed a chow or a high fat (western) diet for 12 weeks. Single-cell aortic preparations were probed with a panel of 35 metal-conjugated antibodies using cytometry by time of flight (CyTOF). Clustering of marker expression on live CD45+ cells from the aortas of ApoE-/- mice identified 13 broad populations of leucocytes. Monocyte, macrophage, type 1 and type 2 conventional dendritic cell (cDC1 and cDC2), plasmacytoid dendritic cell (pDC), neutrophil, eosinophil, B cell, CD4+ and CD8+ T cell, γδ T cell, natural killer (NK) cell, and innate lymphoid cell (ILC) populations accounted for approximately 95% of the live CD45+ aortic cells. Automated clustering algorithms applied to the Lin-CD11blo-hi cells revealed 20 clusters of myeloid cells. Comparison between chow and high fat fed animals revealed increases in monocytes (both Ly6C+ and Ly6C-), pDC, and a CD11c+ macrophage subset with high fat feeding. Concomitantly, the proportions of CD206+ CD169+ subsets of macrophages were significantly reduced as were cDC2.

Conclusions: A CyTOF-based comprehensive mapping of the immune cell subsets within atherosclerotic aortas from ApoE-/- mice offers tools for myeloid cell discrimination within the vascular compartment and it reveals that high fat feeding skews the myeloid cell repertoire toward inflammatory monocyte-macrophage populations rather than resident macrophage phenotypes and cDC2 during atherogenesis.
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http://dx.doi.org/10.1093/cvr/cvy109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054192PMC
August 2018

Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91.

Mol Metab 2017 12 30;6(12):1585-1596. Epub 2017 Sep 30.

NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Biomedical Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark. Electronic address:

Objective: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.

Methods And Results: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.

Conclusions: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.
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http://dx.doi.org/10.1016/j.molmet.2017.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699910PMC
December 2017

The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease.

Antioxid Redox Signal 2018 07 17;29(3):237-256. Epub 2018 Jan 17.

1 Sir William Dunn School of Pathology, University of Oxford , Oxford, Great Britain .

Significance: Great attention has been placed on the link between metabolism and immune function giving rise to the term "immunometabolism." It is widely accepted that inflammation and oxidative stress are key processes that underlie metabolic complications during obesity, diabetes, and atherosclerosis. Therefore, identifying the mechanisms and mediators that are involved in the regulation of both inflammation and metabolic homeostasis is of high scientific and therapeutic interest. Recent Advances: G protein-coupled receptors (GPCRs) that signal in response to metabolites have emerged as attractive therapeutic targets in inflammatory disease. Critical Issues and Future Directions: In this review, we discuss recent findings about the physiological role of the main metabolite-sensing GPCRs, their implication in immunometabolic disorders, their principal endogenous and synthetic ligands, and their potential as drug targets in inflammation and metabolic disease. Antioxid. Redox Signal. 29, 237-256.
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http://dx.doi.org/10.1089/ars.2017.7168DOI Listing
July 2018

Functional diversity of macrophages in vascular biology and disease.

Vascul Pharmacol 2017 12 24;99:13-22. Epub 2017 Oct 24.

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom. Electronic address:

Atherosclerosis is a multifactorial chronic inflammatory disease and is largely responsible for cardiovascular disease, the most common cause of global mortality. The hallmark of atherogenesis is immune activation following lipid accumulation in the arterial wall. In particular, macrophages play a non-redundant role in both the progression and regression of inflammation in the atherosclerotic lesion. Macrophages are remarkably heterogeneous phagocytes that perform versatile functions in health and disease. Their functional diversity in vascular biology is only partially mapped. Targeting macrophages is often highlighted as a therapeutic approach for cancer, metabolic and inflammatory diseases. Future strategies for therapeutic intervention in atherosclerosis may benefit from attempts to reduce local proliferation of pro-inflammatory macrophage subsets or enhance resolution of inflammation. Thus, characterisation of macrophage subsets during atherosclerosis would empower clinical interventions. Therefore, it would be of fundamental importance to understand how pathological factors modulate macrophage activity in order to exploit their use in the treatment of atherosclerosis and other diseases.
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http://dx.doi.org/10.1016/j.vph.2017.10.005DOI Listing
December 2017

Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.

Circulation 2017 Sep 11;136(12):1140-1154. Epub 2017 Jul 11.

From Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom (A.N.S., A.E., J.E.C., C.K., M.S., I.P., P.G., T.K., D.S., M.E.G., S.N.S., I.A.U., C.M.); Department of Bioengineering, Imperial College London, United Kingdom (A.N.S., R.K.); Experimental Cardiovascular Research Unit, Clinical Research Centre, Clinical Sciences Malmö, Lund University, Sweden (A.E., I.G.); Department of Cardiology, Skåne University Hospital, Lund/Malmö, Sweden (A.E., I.G.); and School of Engineering and Materials Science, Queen Mary University of London, United Kingdom (R.K.).

Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions.

Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.

Results: Both lesion and necrotic core size were significantly reduced in ApoEIrf5 mice compared with IRF5-competent ApoE mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c macrophages was evident in ApoEIrf5 mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.

Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598917PMC
September 2017

Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia.

Atherosclerosis 2017 Sep 21;264:100-107. Epub 2017 Jun 21.

Retrotope, Inc, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA. Electronic address:

Background And Aims: Oxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development.

Methods: Transgenic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, were pre-treated with D-PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment.

Results: D-PUFA treatment markedly decreased hepatic and plasma F-isoprostanes (approx. -80%) and prostaglandin Fα (approx. -40%) as compared to H-PUFA treatment. Moreover, D-PUFAs reduced body weight gain during the study (-54%) by decreasing body fat mass gain (-87%) without altering lean mass. D-PUFAs consistently reduced plasma total cholesterol levels (approx. -25%), as reflected in reduced plasma non-HDL-cholesterol (-28%). Additional analyses of hepatic cholesterol metabolism indicated that D-PUFAs reduced the hepatic cholesterol content (-21%). Sterol markers of intestinal cholesterol absorption and cholesterol breakdown were decreased. Markers of cholesterol synthesis were increased. Finally, D-PUFAs reduced atherosclerotic lesion area formation throughout the aortic root of the heart (-26%).

Conclusions: D-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.916DOI Listing
September 2017

Imaging vulnerable plaques by targeting inflammation in atherosclerosis using fluorescent-labeled dual-ligand microparticles of iron oxide and magnetic resonance imaging.

J Vasc Surg 2018 05 22;67(5):1571-1583.e3. Epub 2017 Jun 22.

Regional Vascular Unit, St Mary's Hospital, Imperial College Healthcare National Health Service Trust, Imperial College London, London, United Kingdom.

Objective: Identification of patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and a prelude to clinical sequelae. There are currently no clinical imaging tools to assess the inflammatory activity within plaques. This study characterized inflammation in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) as a magnetic resonance imaging (MRI) probe.

Methods: DT-MPIO were used to detect and characterize inflammatory markers, vascular cell adhesion molecule 1 (VCAM-1). and P-selectin on (1) tumor necrosis factor-α-treated cells by immunocytochemistry and (2) aortic root plaques of apolipoprotein-E deficient mice by in vivo MRI. Furthermore, apolipoprotein E-deficient mice with focal carotid plaques of different phenotypes were developed by means of periarterial cuff placement to allow in vivo molecular MRI using these probes. The association between biomarkers and the magnetic resonance signal in different contrast groups was assessed longitudinally in these models.

Results: Immunocytochemistry confirmed specificity and efficacy of DT-MPIO to VCAM-1 and P-selectin. Using this in vivo molecular MRI strategy, we demonstrated (1) the DT-MPIO-induced magnetic resonance signal tracked with VCAM-1 (r = 0.69; P = .014), P-selectin (r = 0.65; P = .022), and macrophage content (r = 0.59; P = .045) within aortic root plaques and (2) high-risk inflamed plaques were distinguished from noninflamed plaques in the murine carotid artery within a practical clinical imaging time frame.

Conclusions: These molecular MRI probes constitute a novel imaging tool for in vivo characterization of plaque vulnerability and inflammatory activity in atherosclerosis. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid atherosclerotic disease in the future.
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http://dx.doi.org/10.1016/j.jvs.2017.04.046DOI Listing
May 2018

Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques.

J Clin Invest 2017 Apr 20;127(4):1546-1560. Epub 2017 Mar 20.

Background: The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology- and imaging-based definitions of the "vulnerable plaque," necessitating an improved approach for predicting onset of symptoms.

Methods: We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies.

Results: Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study.

Conclusion: The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery.

Funding: UK: British Heart Foundation (BHF); King's BHF Center; and the National Institute for Health Research Biomedical Research Center based at Guy's and St Thomas' NHS Foundation Trust and King's College London in partnership with King's College Hospital. Austria: Federal Ministry for Transport, Innovation and Technology (BMVIT); Federal Ministry of Science, Research and Economy (BMWFW); Wirtschaftsagentur Wien; and Standortagentur Tirol.
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http://dx.doi.org/10.1172/JCI86924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373893PMC
April 2017

Clinical, autoimmune, and psychiatric parameters correlate with sleep disturbance in patients with systemic sclerosis and rheumatoid arthritis.

Clin Exp Rheumatol 2016 Sep-Oct;34 Suppl 100(5):49-55. Epub 2016 May 10.

Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Messina, Italy.

Objectives: Sleep disturbance is an important contributor to poor quality of life in rheumatic disorders. This study aims to test whether clinical, autoimmune and psychological factors are associated with sleep disturbance in systemic sclerosis (SSc) compared to rheumatoid arthritis (RA) patients and controls.

Methods: 101 female subjects (SSc=33, RA=34, healthy controls=34) participated in this observational, cross-sectional, parallel group study. Sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). Other assessments included the visual analogue scale (VAS) for pain, 36-item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). Clinical parameters, therapeutic regimen, and serologic status were recorded.

Results: In SSc patients, PSQI scores were higher than in RA patients and controls. Linear regression analysis showed that in SSc patients PSQI scores was associated with BDI, disease duration, modified Rodnan skin score and VAS, while DAS28 and BDI were associated with PSQI scores in RA patients. Anti-Scl70 and ANA positive SSc patients showed higher PSQI scores compared to those ANA positive only, while no differences were observed in RA patients classified according to rheumatoid factor positivity. SSc patients treated with immunosuppressants had lower PSQI scores compared to those not on therapy, whereas only corticosteroid treatment was significantly associated with higher PSQI scores in RA patients. RA patients with disease activity higher than moderate (DAS28≥3.2) had higher PSQI scores than those with lower than moderate (DAS28<3.2).

Conclusions: Longitudinal studies are needed to identify disease-specific patterns associated with sleep disturbances and the influence on sleep function induced by immunosuppressive therapy among rheumatic patients.
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January 2017

Anti-TNF Therapy.

Microbiol Spectr 2016 08;4(4)

Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Botnar Research Centre, Headington, Oxford OX3 7LD, United Kingdom.

Tumor necrosis factor (TNF) is one of the most important cytokines produced by macrophages. TNF is a very important component of host defense, released very rapidly after all types of injuries and stimuli. The kinetics of TNF release are short, and so it is perhaps not surprising that prolonged TNF production is associated with pathology. This was first elucidated in rheumatoid arthritis but extends to other chronic inflammatory diseases such as Crohn's disease and psoriasis. In this chapter, the discovery of anti-TNF therapy is reviewed, with its benefit but also its limitations. The potential of anti-TNF therapy in other diseases, e.g., cardiovascular and fibrosis, is discussed, as is the opportunity to define ways of blocking TNF synthesis.
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http://dx.doi.org/10.1128/microbiolspec.MCHD-0022-2015DOI Listing
August 2016

Role and analysis of monocyte subsets in cardiovascular disease. Joint consensus document of the European Society of Cardiology (ESC) Working Groups "Atherosclerosis & Vascular Biology" and "Thrombosis".

Thromb Haemost 2016 Sep 14;116(4):626-37. Epub 2016 Jul 14.

Dr. Michael Hristov, LMU Munich - Cardiovascular Prevention, Pettenkoferstr. 9, 80336 Munich, Germany, Tel.: +49 89 4400 54350, Fax: +49 89 4400 54352, E-mail:

Monocytes as cells of the innate immunity are prominently involved in the development of atherosclerotic lesions. The heterogeneity of blood monocytes has widely been acknowledged by accumulating experimental and clinical data suggesting a differential, subset-specific contribution of the corresponding subpopulations to the pathology of cardiovascular and other diseases. This document re-evaluates current nomenclature and summarises key findings on monocyte subset biology to propose a consensus statement about phenotype, separation and quantification of the individual subsets.
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http://dx.doi.org/10.1160/TH16-02-0091DOI Listing
September 2016

Multi-analyte profiling in human carotid atherosclerosis uncovers pro-inflammatory macrophage programming in plaques.

Thromb Haemost 2016 05 14;115(5):1064-72. Epub 2016 Jan 14.

Claudia Monaco, Professor of Cardiovascular Inflammation, Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK, Tel.: +44 1865 612 636, Fax: +44 1865 612 601, E-mail:

Molecular characterisation of vulnerable atherosclerosis is necessary for targeting functional imaging and plaque-stabilising therapeutics. Inflammation has been linked to atherogenesis and the development of high-risk plaques. We set to quantify cytokine, chemokine and matrix metalloproteinase (MMP) protein production in cells derived from carotid plaques to map the inflammatory milieu responsible for instability. Carotid endarterectomies from carefully characterised symptomatic (n=35) and asymptomatic (n=32) patients were enzymatically dissociated producing mixed cell type atheroma cell suspensions which were cultured for 24 hours. Supernatants were interrogated for 45 analytes using the Luminex 100 platform. Twenty-nine of the 45 analytes were reproducibly detectable in the majority of donors. The in vitro production of a specific network of mediators was found to be significantly higher in symptomatic than asymptomatic plaques, including: tumour necrosis factor α, interleukin (IL) 1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), CCL5, CCL20, CXCL9, matrix metalloproteinase (MMP)-3 and MMP-9. Ingenuity pathway analysis of differentially expressed analytes between symptomatic and asymptomatic patients identified a number of key biological pathways (p< 10(-25)). In conclusion, the carotid artery plaque culprit of ischaemic neurological symptoms is characterised by an inflammatory milieu favouring inflammatory cell recruitment and pro-inflammatory macrophage polarisation.
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http://dx.doi.org/10.1160/TH15-08-0650DOI Listing
May 2016

Spontaneous Tricuspid Valve Chordal Rupture in Idiopathic Pulmonary Hypertension.

Echocardiography 2016 Mar 13;33(3):472-5. Epub 2015 Dec 13.

Echocardiography Laboratory, MDP, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.

Rupture of tricuspid valve is unusual, occurring mainly in the setting of blunt trauma or endomyocardial biopsy. Spontaneous tricuspid valve chordal rupture is particularly rare. We report herein a case of a patient with severe pulmonary hypertension, on the lung transplantation waiting list, who presented with spontaneous chordal rupture, exacerbation of tricuspid insufficiency and worsening of clinical status. Diagnosis and treatment, along with possible mechanisms for this complication, are discussed.
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http://dx.doi.org/10.1111/echo.13130DOI Listing
March 2016

Low shear stress induces M1 macrophage polarization in murine thin-cap atherosclerotic plaques.

J Mol Cell Cardiol 2015 Dec 30;89(Pt B):168-72. Epub 2015 Oct 30.

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom. Electronic address:

Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE(-/-)) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE(-/-) mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming.
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http://dx.doi.org/10.1016/j.yjmcc.2015.10.034DOI Listing
December 2015

Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development.

Proc Natl Acad Sci U S A 2015 Oct 5;112(42):13033-8. Epub 2015 Oct 5.

Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;

Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE(-/-) mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE(-/-) mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not l-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE(-/-) mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD.
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http://dx.doi.org/10.1073/pnas.1517820112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620898PMC
October 2015

B regulatory cells are increased in hypercholesterolaemic mice and protect from lesion development via IL-10.

Thromb Haemost 2015 Oct 11;114(4):835-47. Epub 2015 Jun 11.

Claudia Monaco, Kennedy Institute of Rheumatology, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK, Tel.: + 44 1865 612 636, Fax: + 44 1865 612 601, E-mail:

Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (B(reg)) have been described. In experimental arthritis and lupus-like disease, B(reg) are contained within the CD21(hi)CD23(hi)CD24(hi) B cell pool. The existence and role of B(reg) in vascular disease is not known. We sought to investigate the existence, identity and location of B(reg) in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E(-/-) (ApoE(-/-)) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE(-/-) mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21(hi)CD23(hi)CD24(hi) B cells are unexpectedly increased in the draining LNs of ApoE(-/-) mice. Adoptive transfer of LN-derived B2-B cells or purified CD21(hi)CD23(hi)CD24(hi) B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-B(reg) subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease.
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http://dx.doi.org/10.1160/TH14-12-1084DOI Listing
October 2015

Novel methodologies for biomarker discovery in atherosclerosis.

Eur Heart J 2015 Oct 5;36(39):2635-42. Epub 2015 Jun 5.

Ludwig-Maximilians-University, G02.523, Heidelberglaan 100, 3584CX Munich, Germany German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction.
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http://dx.doi.org/10.1093/eurheartj/ehv236DOI Listing
October 2015