Publications by authors named "Ziad Mallat"

205 Publications

"Plaque erosion" or the danger of eerily quiet appearance.

Atherosclerosis 2021 02 5;318:43-44. Epub 2021 Jan 5.

Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK; Université de Paris, Inserm U970, Paris-Cardiovascular Research Center, Paris, France.

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.022DOI Listing
February 2021

Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function After Myocardial Infarction Through Kynurenine.

Circulation 2021 Feb 4;143(6):566-580. Epub 2020 Dec 4.

Université de Paris, Paris-Centre de Recherche Cardiovasculaire (PARCC), Institut National de la Santé et de la Recherche Médicale, France (N.-J.M., M.C., I.G., K.-Y.H., M.B., C.K., Y.S., M.R., L.L., M.L., J.V., Z.M., A.T., H.A.-O., J.-S.H., J.-S.S., S.T.).

Background: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI.

Methods: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction.

Results: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism.

Conclusions: These data suggest that IDO could constitute a new therapeutic target during acute MI.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050301DOI Listing
February 2021

TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm.

J Clin Invest 2021 Jan;131(2)

Université de Paris, Inserm U970, Paris-Cardiovascular Research Center, Paris, France.

The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.
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http://dx.doi.org/10.1172/JCI142468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810476PMC
January 2021

NR4A1 Deletion in Marginal Zone B Cells Exacerbates Atherosclerosis in Mice-Brief Report.

Arterioscler Thromb Vasc Biol 2020 11 10;40(11):2598-2604. Epub 2020 Sep 10.

Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (M.N., G.B., L.C.-B., T.X.Z., L.M., J.H., N.F., A.P.S., Z.M.).

Objective: NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 (nerve growth factor IB) is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding mice a Western diet substantially increased expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated mice with complete B- or specific MZB-cell deletion of . Complete B-cell deletion of led to increased atherosclerosis, which was accompanied by increased T follicular helper cell-germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of increased atherosclerosis in association with an increased T follicular helper-germinal center response but without any impact on serum cholesterol or triglyceride levels. MZB cells showed decreased PDL1 (programmed death ligand-1) expression, which may have contributed to the enhanced T follicular helper response.

Conclusions: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.
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http://dx.doi.org/10.1161/ATVBAHA.120.314607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571845PMC
November 2020

IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture.

Clin Sci (Lond) 2020 06;134(11):1191-1218

Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 μg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.
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http://dx.doi.org/10.1042/CS20200402DOI Listing
June 2020

Thymic stromal lymphopoietin is a key cytokine for the immunomodulation of atherogenesis with Freund's adjuvant.

J Cell Mol Med 2020 05 13;24(10):5731-5739. Epub 2020 Apr 13.

Paris Cardiovascular Research Center, INSERM U970, Paris, France.

Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E-deficient (ApoE ) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7-like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti-atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1β at the site of injection. In male mice, CFA-induced TSLP occurred in immigrated monocytes-and not epithelial cells-and was dependent on NLRP3 inflammasome activation and IL1β-signalling. In females, CFA-induced TSLP was independent of IL1β and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR mice, with increased INFγ/IL4 ratio compared with wild-type controls. To test whether TSLP contributes to the anti-atherogenic effects of Freund's adjuvant, we treated ApoE and ApoE /TSLPR mice with either CFA/IFA or PBS. ApoE mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE /TSLPR mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune-modulating effects via TSLP induction. TSLP-TSLPR signalling is critical for CFA/IFA-mediated attenuation of atherosclerosis.
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http://dx.doi.org/10.1111/jcmm.15235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214169PMC
May 2020

Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

Immunity 2020 05 8;52(5):782-793.e5. Epub 2020 Apr 8.

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK; Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France. Electronic address:

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.
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http://dx.doi.org/10.1016/j.immuni.2020.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237885PMC
May 2020

The year 2019 in Atherosclerosis.

Atherosclerosis 2020 04 19;299:67-75. Epub 2020 Mar 19.

Institute of Clinical Chemistry, University of Zurich, University Hospital of Zurich, Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.018DOI Listing
April 2020

Suppression of Hematopoiesis in Recurrent Myocardial Infarction: A Deadly Silence.

J Am Coll Cardiol 2020 03;75(8):916-918

Université de Paris, PARCC, INSERM, F-75015 Paris, France.

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http://dx.doi.org/10.1016/j.jacc.2020.01.008DOI Listing
March 2020

2019 Plenary Lecture: Interleukin-2 Therapy in Cardiovascular Disease: The Potential to Regulate Innate and Adaptive Immunity.

Arterioscler Thromb Vasc Biol 2020 04 6;40(4):853-864. Epub 2020 Feb 6.

From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (T.X.Z., S.A.N., Z.M.).

Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor β, to regulate or suppress pathogenic immune responses. Type-2 innate lymphoid cells have an important role in type-2 immune responses and tissue repair through secreting interleukins 5 and 13, as well as a variety of biological mediators and growth factors. Intriguingly, interleukin-2 has emerged as a common cytokine, which can be harnessed to upregulate both cell types, and also has important translational consequences as clinical trials are ongoing for its use in cardiovascular disease. Here, we briefly review the biology of these regulatory immune cell types, discuss the preclinical and clinical evidence for their functions in cardiovascular disease, examine the prospects for clinical translation and current ongoing trials, and finally, postulate how overlap in the mechanisms of upregulation may be leveraged in future treatments for patients.
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http://dx.doi.org/10.1161/ATVBAHA.119.312287DOI Listing
April 2020

The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection.

Malar J 2019 Nov 29;18(1):381. Epub 2019 Nov 29.

Department of Life Sciences, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ, UK.

Background: Malaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes. Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests erythrocyte biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties demanding its interrogation as a potential mediator of resistance to merozoite invasion of the erythrocyte.

Methods: Biophysical measurements of erythrocyte deformability by flicker spectroscopy were used to assess changes in erythrocyte bending modulus on forced integration of cholesterol and how these artificial changes affect invasion by human Plasmodium falciparum merozoites. To validate these observations in a natural context, either murine Plasmodium berghei or human Plasmodium falciparum merozoites were tested for their ability to invade erythrocytes from a hypercholesterolaemic mouse model or human clinical erythrocyte samples deriving from patients with a range of serum cholesterol concentrations, respectively.

Results: Erythrocyte bending modulus (a measure of deformability) was shown to be markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. In an in vitro infection context, however, erythrocytes taken from hypercholesterolaemic mice or from human clinical samples with varying serum cholesterol levels showed little difference in their susceptibility to merozoite invasion. Explaining this, membrane cholesterol levels in both mouse and human hypercholesterolaemia erythrocytes were subsequently found to be no different from matched normal serum controls.

Conclusions: Based on these observations, serum cholesterol does not appear to impact on erythrocyte susceptibility to merozoite entry. Indeed, no relationship between serum cholesterol and cholesterol content of the erythrocyte is apparent. This work, nonetheless, suggests that native polymorphisms which do affect membrane lipid composition would be expected to affect parasite entry. This supports investigation of erythrocyte biophysical properties in endemic settings, which may yet identify naturally protective lipid-related polymorphisms.
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http://dx.doi.org/10.1186/s12936-019-3016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884832PMC
November 2019

Editorial: Inflammation and Reparative Process After Cardiac Injury.

Front Cardiovasc Med 2019 8;6:162. Epub 2019 Nov 8.

Université de Paris, PARCC, INSERM, Paris, France.

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http://dx.doi.org/10.3389/fcvm.2019.00162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856946PMC
November 2019

Impaired Autophagy in CD11b Dendritic Cells Expands CD4 Regulatory T Cells and Limits Atherosclerosis in Mice.

Circ Res 2019 11 15;125(11):1019-1034. Epub 2019 Oct 15.

From the Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom (M.C., J.R., F.L., D.T., S.N., Y.L., L.M., J.H., Z.M.).

Rationale: Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells, and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit.

Objective: Dendritic cells (DCs) are at the crossroad of innate and adaptive immune responses and profoundly modulate the development of atherosclerosis. Intriguingly, the role of autophagy in DC function during atherosclerosis and how the autophagy process would impact disease development has not been addressed.

Methods And Results: Here, we show that the autophagic flux in atherosclerosis-susceptible (low-density lipoprotein receptor-deficient) mice is substantially higher in splenic and aortic DCs compared with macrophages and is further activated under hypercholesterolemic conditions. RNA sequencing and functional studies on selective cell populations reveal that disruption of autophagy through deletion of differentially affects the biology and functions of DC subsets in mice under high-fat diet. deficient CD11b DCs develop a TGF (transforming growth factor)-β-dependent tolerogenic phenotype and promote the expansion of regulatory T cells, whereas no such effects are seen with deficient CD8α DCs. deletion in DCs (all CD11c-expressing cells) expands aortic regulatory T cells in vivo, limits the accumulation of T helper cells type 1, and reduces the development of atherosclerosis in mice. In contrast, no such effects are seen when is deleted selectively in conventional CD8α DCs and CD103 DCs. Total T-cell or selective regulatory T-cell depletion abrogates the atheroprotective effect of deficient DCs.

Conclusions: In contrast to its proatherogenic role in macrophages, autophagy disruption in DCs induces a counter-regulatory response that maintains immune homeostasis in mice under high-fat diet and limits atherogenesis. Selective modulation of autophagy in DCs could constitute an interesting therapeutic target in atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844650PMC
November 2019

Regulating heart repair with cardiac-specific T lymphocytes.

Authors:
Ziad Mallat

J Clin Invest 2019 11;129(11):4587-4589

Cardiac tissue necrosis secondary to coronary artery occlusion is one of the most common and deadly sterile injuries in developed countries. In this issue of the JCI, Rieckmann et al. identified and characterized antigen-specific CD4+ T helper (Th) cells that developed in the context of myocardial infarction (MI) in mice. They showed that myosin heavy chain α (MYHCA) is a dominant cardiac autoantigen and that T cells with T cell receptor (TCR) specificity to MYHCA acquired a Treg phenotype when adoptively transferred into infarcted mice, which mediated a cardioprotective healing response. Thus, Rieckmann et al. showed that an acute ischemic insult to the heart, which induces sterile inflammation, promoted, rather than limited, protective T cell autoimmunity. Notably, strategies that support an antigen-specific Treg response may limit the immune-inflammatory response and promote cardiac repair after acute MI.
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http://dx.doi.org/10.1172/JCI132441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819086PMC
November 2019

Beating (T-lymphocyte driven) atherosclerosis with B- and T-lymphocyte attenuator.

Cardiovasc Res 2020 02;116(2):251-252

Division of Cardiovascular Medicine, Department of Medicine, Box 157 Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

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http://dx.doi.org/10.1093/cvr/cvz184DOI Listing
February 2020

Vascular smooth muscle cells in atherosclerosis.

Nat Rev Cardiol 2019 12 26;16(12):727-744. Epub 2019 Jun 26.

Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
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http://dx.doi.org/10.1038/s41569-019-0227-9DOI Listing
December 2019

Keeping our hearts 'NEAT'?

Cardiovasc Res 2019 11;115(13):1813-1814

Division of Cardiovascular Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK.

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http://dx.doi.org/10.1093/cvr/cvz149DOI Listing
November 2019

MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report.

Arterioscler Thromb Vasc Biol 2019 08 6;39(8):1645-1651. Epub 2019 Jun 6.

From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., H.L.C., S.T., S.A.N., J.H., X.Y., A.J.F., Z.M., X.L.).

Objective: MARK4 (microtubule affinity-regulating kinase 4) regulates NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome activation. The aim of the study is to examine the role of MARK4 in hematopoietic cells during atherosclerosis.

Methods And Results: We show increased MARK4 expression in human atherosclerotic lesions compared with adjacent areas. MARK4 is coexpressed with NLRP3, and they colocalize in areas enriched in CD68-positive but α-SMA (α-smooth muscle actin)-negative cells. Expression of MARK4 and NLRP3 in the atherosclerotic lesions is associated with the production of active IL (interleukin)-1β and IL-18. To directly assess the role of hematopoietic MARK4 in NLRP3 inflammasome activation and atherosclerotic plaque formation, Ldlr (low-density lipoprotein receptor)-deficient mice were lethally irradiated and reconstituted with either wild-type or Mark4-deficient bone marrow cells, and were subsequently fed a high-fat diet and cholesterol diet for 9 weeks. Mark4 deficiency in bone marrow cells led to a significant reduction of lesion size, together with decreased circulating levels of IL-18 and IFN-γ (interferon-γ). Furthermore, Mark4 deficiency in primary murine bone marrow-derived macrophages prevented cholesterol crystal-induced NLRP3 inflammasome activation, as revealed by reduced caspase-1 activity together with reduced production of IL-1β and IL-18.

Conclusions: MARK4-dependent NLRP3 inflammasome activation in the hematopoietic cells regulates the development of atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.119.312478DOI Listing
August 2019

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling.

Front Immunol 2019 8;10:921. Epub 2019 May 8.

Department of Medicine, School of Clinical Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (T) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.
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http://dx.doi.org/10.3389/fimmu.2019.00921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519317PMC
September 2020

Disruption of the CCL1-CCR8 axis inhibits vascular Treg recruitment and function and promotes atherosclerosis in mice.

J Mol Cell Cardiol 2019 07 21;132:154-163. Epub 2019 May 21.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBER-CV), Spain. Electronic address:

The CC chemokine 1 (CCL1, also called I-309 or TCA3) is a potent chemoattractant for leukocytes that plays an important role in inflammatory processes and diseases through binding to its receptor CCR8. Here, we investigated the role of the CCL1-CCR8 axis in atherosclerosis. We found increased expression of CCL1 in the aortas of atherosclerosis-prone fat-fed apolipoprotein E (Apoe)-null mice; moreover, in vitro flow chamber assays and in vivo intravital microscopy demonstrated an essential role for CCL1 in leukocyte recruitment. Mice doubly deficient for CCL1 and Apoe exhibited enhanced atherosclerosis in aorta, which was associated with reduced plasma levels of the anti-inflammatory interleukin 10, an increased splenocyte Th1/Th2 ratio, and a reduced regulatory T cell (Treg) content in aorta and spleen. Reduced Treg recruitment and aggravated atherosclerosis were also detected in the aortas of fat-fed low-density lipoprotein receptor-null mice treated with CCR8 blocking antibodies. These findings demonstrate that disruption of the CCL1-CCR8 axis promotes atherosclerosis by inhibiting interleukin 10 production and Treg recruitment and function.
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http://dx.doi.org/10.1016/j.yjmcc.2019.05.009DOI Listing
July 2019

B Cell Fcγ Receptor IIb Modulates Atherosclerosis in Male and Female Mice by Controlling Adaptive Germinal Center and Innate B-1-Cell Responses.

Arterioscler Thromb Vasc Biol 2019 07 16;39(7):1379-1389. Epub 2019 May 16.

From the Division of Cardiovascular Medicine (J.B.-C., A.F., T.B., L.M., D.T., M.N., J.H., M.B., J.L., Z.M., A.P.S.), Department of Medicine, University of Cambridge, United Kingdom.

Objective- Investigate the impact of modulating B cell FcγRIIb (Fcγ receptor IIb) expression on atherosclerosis. Approach and Results- Western diet-induced atherosclerosis was assessed in Ldlr or Apoe mice with B cell-specific overexpression of FcγRIIb or with an FcγRIIb promoter mutation that alters FcγRIIb expression in germinal center (GC) B cells. In males, overexpression of FcγRIIb on B cells severely reduced activated, class switched B cell responses, as indicated by reductions in GC B cells, plasma cells, and serum IgG but not IgM antibodies. Male mice overexpressing FcγRIIb developed less atherosclerosis, suggesting a pathogenic role for GC B cell IgG responses. In support of this hypothesis, male mice with a promoter polymorphism-driven reduction in FcγRIIb on GC B cells but not plasma cells have a converse phenotype of enhanced GC responses and IgG2c antibodies and enhanced atherosclerosis. IgG2c significantly enhanced TNF (tumor necrosis factor) secretion by CD11b CD11c cells expressing the high-affinity receptor FcγRIV. In females, overexpression of FcγRIIb on B cells not only reduced GC B cell responses but also substantially reduced B-1 cells and IgM antibodies, which translated into acceleration of atherosclerosis. Promoter-driven reduction in FcγRIIb did not alter GC B cell responses in females and, therefore, had no impact on atherosclerosis. Conclusions- B cell FcγRIIb differentially alters proatherogenic adaptive GC B cell and atheroprotective innate B-1 responses in male and female mice fed a western diet. Our results highlight the importance of a better understanding and ability to selectively target B cell responses in future immunotherapeutic approaches against human cardiovascular disease. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/ATVBAHA.118.312272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636804PMC
July 2019

Targeting the Immune System in Atherosclerosis: JACC State-of-the-Art Review.

J Am Coll Cardiol 2019 04;73(13):1691-1706

Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Atherosclerosis has long been known as an inflammatory disease. However, whether targeting inflammation improves outcomes was unproven until the recent results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). In this review, we reflect on why it has taken a long time to prove the inflammatory hypothesis of atherosclerosis and derive important lessons for the future. In particular, we discuss the off-target immune-modulatory effects of approved cardiovascular therapies, review the attempted anti-inflammatory therapies including the recently published CIRT (Cardiovascular Inflammation Reduction Trial), and discuss the likely reasons for their failures. We further build on CANTOS to review the immune-modulatory therapies for atherosclerosis currently in trials, and discuss the likelihood of their added value as well as the potential hazard associated with their use. We finally argue for a critical approach to the use of animal models, coupled with the use of humans as model organisms to accelerate the identification of the most appropriate targets.
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http://dx.doi.org/10.1016/j.jacc.2018.12.083DOI Listing
April 2019

Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1149-1159

From the Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (M.C., J.C., J.R., F.L., A.L.T., A.F., J.H., M.R.B., H.F.J., Z.M.).

Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair.
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http://dx.doi.org/10.1161/ATVBAHA.118.311727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544538PMC
June 2019

Differential micro-RNA expression in diabetic patients with abdominal aortic aneurysm.

Biochimie 2019 Jul 26;162:1-7. Epub 2019 Mar 26.

Université Côte d'Azur, CHU, Inserm U1065, C3M, Nice, France; Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, CB20 SZ, UK; Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, 75015, Paris, France; Department of Clinical Biochemistry, University Hospital of Nice, France. Electronic address:

Objectives: The potential implication of micro-RNAs (miRs) in the negative association between diabetes and abdominal aortic aneurysm (AAA) has so far never been addressed. The aim of this study was to compare miR expression between diabetic and non-diabetic patients with AAA.

Methods: Ten diabetic patients were prospectively included and compared to 10 age- and sex-matched non-diabetic patients with infrarenal AAA. A profiling analysis of 752 human miRs was performed from peripheral blood mononuclear cells (PBMCs) using miRCURY LNA Universal RT microRNA PCR (Exiqon- Qiagen). miR that showed significant differential expression (P < 0.05) were selected and further analyzed in the entire cohort in sera, plasma and aneurysmal aortic tissues.

Results: Four miRs were significantly differentially expressed in PBMCs of diabetic patients compared to non-diabetics: 3 were upregulated (miR-144-3p, 20a-5p and 188-3p) and 1 downregulated (miR-548k). miR-144-3p and miR-548k were also increased in aneurysmal tissue and miR-20a-5p was increased in serum. The expression of miR-20a-5p in PBMCs was correlated with fructosamine concentration (r = 0.62, p = 0.006).

Conclusions: Even if further studies are required to determine their direct role in AAA, these miRs could represent interesting new targets.
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http://dx.doi.org/10.1016/j.biochi.2019.03.012DOI Listing
July 2019

Transforming growth factor β neutralization finely tunes macrophage phenotype in elastase-induced abdominal aortic aneurysm and is associated with an increase of arginase 1 expression in the aorta.

J Vasc Surg 2019 08 18;70(2):588-598.e2. Epub 2019 Feb 18.

Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Paris, France.

Objective: Macrophages play a critical role in the initiation and progression of abdominal aortic aneurysm (AAA) and are classically distinguished into M1 "proinflammatory" and M2 "anti-inflammatory" macrophages. Topical application of elastase associated with transforming growth factor β (TGF-β) systemic neutralization reproduces the main pathologic features of human AAA, offering a new model to investigate their role. The aim of this study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-β and whether blocking of TGF-β activity affects macrophage phenotype and the expression of the M2 marker arginase 1 (ARG1).

Methods: C57Bl/6J male mice (6-8 weeks old) were randomly assigned to three experimental groups: mice that had local application of heat-inactivated elastase or elastase and mice that had elastase application and received injection of anti-TGF-β (elastase + anti-TGF-β group). Monocyte-macrophage depletion was achieved in the elastase + anti-TGF-β group using liposome clodronate. Macrophage phenotype was characterized by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. Human infrarenal AAA tissues (n = 10) were obtained to analyze ARG1 expression.

Results: Analysis of gene expression in the infrarenal aortic wall revealed that after 14 days, no significant difference for the expression of CCL2, NOS2, and Ym1/2 was observed in the elastase group compared with the elastase + anti-TGF-β group, whereas the expression of ARG1, interleukin (IL) 1β, and IL-6 was significantly increased. Macrophage depletion in the elastase + anti-TGF-β group led to a significant decrease of IL-1β, IL-6, ARG1, and Ym1/2 gene expression. Immunofluorescent staining confirmed that TGF-β neutralization significantly enhanced ARG1 protein expression in the aneurysmal tissue. Flow cytometry analysis revealed an increase of macrophages expressing ARG1 in the aorta of mice treated with elastase + anti-TGF-β compared with the elastase group, and their proportion increased with aneurysmal dilation. In humans, ARG1 protein expression was increased in aneurysmal tissues compared with controls, and positive cells were mainly found in the adventitia.

Conclusions: TGF-β neutralization finely tunes macrophage phenotype in elastase-induced AAA and leads to an increase in ARG1 gene and protein expression in the aortic wall. Even if further studies are required to elucidate its role in AAA development, ARG1 could represent a new prognostic or therapeutic target in aneurysmal disease.
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http://dx.doi.org/10.1016/j.jvs.2018.09.045DOI Listing
August 2019

Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates.

Circ Genom Precis Med 2019 02;12(2):e002413

Division of Cardiovascular Medicine (M.C., F.L., J.R., C.G., A.F., J.H., Z.M.), University of Cambridge, United Kingdom.

Background: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection.

Methods: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death.

Results: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05).

Conclusions: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.
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http://dx.doi.org/10.1161/CIRCGEN.118.002413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383754PMC
February 2019

MicroRNA-21 Deficiency Alters the Survival of Ly-6C Monocytes in ApoE Mice and Reduces Early-Stage Atherosclerosis-Brief Report.

Arterioscler Thromb Vasc Biol 2019 02;39(2):170-177

From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France.

Objective- To determine the role of microRNA-21 (miR-21) on the homeostasis of monocyte subsets and on atherosclerosis development in ApoE (apolipoprotein E) mice. Approach and Results- In ApoE mice, miR-21 expression was increased in circulating Ly-6C nonclassical monocytes in comparison to Ly-6C monocytes. The absence of miR-21 significantly altered the survival and number of circulating Ly-6C nonclassical monocytes in ApoE mice. In the early stages of atherosclerosis, the absence of miR-21 limited lesion development both in the aortic sinus (by almost 30%) and in the aorta (by almost 50%). This was associated with less monocyte availability in circulation and increased apoptosis of local macrophages in plaques. At later stages of atherosclerosis, lesion size in the aortic root was similar in ApoE and ApoE miR-21 mice, but plaques showed a less stable phenotype (larger necrotic cores) in the latter. The loss of protection in advanced stages was most likely because of excessive inflammatory apoptosis related to an impairment of local efficient efferocytosis. Conclusions- Gene deletion of miR-21 in ApoE mice alters Ly-6C nonclassical monocytes homeostasis and contribute to limit early-stage atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.118.311942DOI Listing
February 2019

The role of B cells in atherosclerosis.

Nat Rev Cardiol 2019 03;16(3):180-196

Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.

The cardiovascular system is subject to hyperlipidaemic, inflammatory, and pro-oxidant stressors. Over time, these factors drive prevalent chronic diseases, of which atherosclerosis is most prominent and accounts for the majority of deaths globally. Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. The power, inducibility, and adaptability of the antibody repertoire require an equally complex range of control measures. Defects and chronic perturbations in these checkpoints lead to inappropriate antibody responses, which might have important roles in shaping the development and outcome of atherosclerotic disease. A unique aspect related to atherosclerosis is the prominent role of natural antibodies, specifically those binding to the oxidized epitopes that are abundant on modified lipoproteins and cellular debris. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted. For these reasons, a deeper understanding of how B cells influence atherosclerotic plaque development is being pursued with the hope of providing novel B cell-targeted interventions to prevent inflammation-driven cardiovascular events.
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http://dx.doi.org/10.1038/s41569-018-0106-9DOI Listing
March 2019

IL-33 (Interleukin 33)/sST2 Axis in Hypertension and Heart Failure.

Hypertension 2018 10;72(4):818-828

Department of Pharmacology and Toxicology (G.W.B.), School of Medicine, University of Mississippi Medical Center, Jackson.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11157DOI Listing
October 2018

Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial.

BMJ Open 2018 09 17;8(9):e022452. Epub 2018 Sep 17.

Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge Medicine, Cambridge, UK.

Introduction: Inflammation and dysregulated immune responses play a crucial role in atherosclerosis, underlying ischaemic heart disease (IHD) and acute coronary syndromes (ACSs). Immune responses are also major determinants of the postischaemic injury in myocardial infarction. Regulatory T cells (CD4CD25FOXP3; Treg) induce immune tolerance and preserve immune homeostasis. Recent in vivo studies suggested that low-dose interleukin-2 (IL-2) can increase Treg cell numbers. Aldesleukin is a human recombinant form of IL-2 that has been used therapeutically in several autoimmune diseases. However, its safety and efficacy is unknown in the setting of coronary artery disease.

Method And Analysis: Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes is a single-centre, first-in-class, dose-escalation, two-part clinical trial. Patients with stable IHD (part A) and ACS (part B) will be randomised to receive either IL-2 (aldesleukin; dose range 0.3-3×10 IU) or placebo once daily, given subcutaneously, for five consecutive days. Part A will have five dose levels with five patients in each group. Group 1 will receive a dose of 0.3×10 IU, while the dose for the remaining four groups will be determined on completion of the preceding group. Part B will have four dose levels with eight patients in each group. The dose of the first group will be based on part A. Doses for each of the subsequent three groups will similarly be determined after completion of the previous group. The primary endpoint is safety and tolerability of aldesleukin and to determine the dose that increases mean circulating Treg levels by at least 75%.

Ethics And Dissemination: The study received a favourable opinion by the Greater Manchester Central Research Ethics Committee, UK (17/NW/0012). The results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report.

Trial Registration Number: NCT03113773; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144322PMC
September 2018