Soraya Taleb - Academia.edu (original) (raw)

Papers by Soraya Taleb

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Archives of Cardiovascular Diseases Supplements, May 1, 2021

Nature Communications, Dec 23, 2022

Arteriosclerosis, Thrombosis, and Vascular Biology, May 1, 2018

Introduction: There are accumulating evidences that innate and adaptive immunity play a major rol... more Introduction: There are accumulating evidences that innate and adaptive immunity play a major role in the development of atherosclerosis. Pattern-recognition receptors (PRRs) engagement including Toll-like receptors and Dectins are involved in the modulation of immune responses and atherosclerosis development but little is known about downstream signaling pathways. Card9 for Caspase recruitment domain-containing protein-9, is an adaptor protein expressed by antigen presenting cells required for PRRs-induced activation of myeloid cells. We hypothesized that Card9 pathway regulates systemic immune response and impacts on the development of atherosclerosis. Method and results: To evaluate the effect of Card9 deficiency on experimental atherosclerosis, Ldlr -/- mice were lethally irradiated and reconstituted with Card9 -/- or Card9 +/+ bone marrow cells and put under a high fat diet during 8 weeks. Animal weight and cholesterolemia were not different between groups. We observed an increase of atherosclerosis plaque size in the aortic sinus in chimeric Ldlr -/- Card9 -/- mice compared to chimeric Ldlr -/- Card9 +/+ mice (+32%, P=0.04). A more inflammatory plaque phenotype was found in chimeric Ldlr -/- Card9 -/- mice compared to control mice with an increase in both macrophage accumulation (+86%, P=0.0005) and necrotic core size (+102%, P=0.006). Card9 deficiency induced a deviation of the systemic immune response toward a pro-inflammatory profile. Lps/Ifn-γ-stimulated Card9 -/- bone marrow-derived macrophages (BMDM) produced less IL-10 (-22%, P&lt;0.05) than Card9 +/+ BMDM. Lps/Ifn-γ-stimulated splenocytes from chimeric LDLr -/- Card9 -/- mice produced more IL-12p70 (+151%, P&lt;0.01) than splenocytes from control mice. Anti-CD3 stimulated CD4 + T cells from chimeric Ldlr -/- Card9 -/- mice produced less Ifn-γ (-92%, P&lt;0.05) and IL-17A (-100%, P&lt;0.05) than control CD4 + T cells. A second atherosclerosis mouse model ApoE -/- Card9 -/- confirmed the protective role of Card9 with an increase in both atherosclerosis plaque size and macrophage accumulation in ApoE -/- Card9 -/- mice compared to ApoE -/- Card9 +/+ mice. Conclusion: Card9 deficiency accelerated atherosclerosis development in mice and induced a more inflammatory plaque phenotype.

Archives of Cardiovascular Diseases Supplements, Apr 1, 2018

Arteriosclerosis, Thrombosis, and Vascular Biology, May 1, 2017

Background: Abdominal aortic aneurysm (AAA) carries important morbidity and mortality and is resi... more Background: Abdominal aortic aneurysm (AAA) carries important morbidity and mortality and is resistant to medical therapy. Current experimental models do not accurately reproduce the major features of the human disease. There are 2 major categories of mouse models of AAA: those that induce medial dissection, which is not a major characteristic of human AAA, and those that induce aortic dilatation but are self-contained and do not progress to rupture. Methods: We hypothesized that blockade of TGFβ activity, a guardian of vascular integrity and immune homeostasis, and a major causal factor in genetically triggered thoracic aortic aneurysms in humans, would impair vascular healing in models of ‘non-dissecting’ abdominal aortic dilatation, and would lead to continuous aneurysmal growth until rupture. We tested this hypothesis in the elastase-induced abdominal aortic dilatation model in mice. We analyzed AAA development and progression using ultrasound in vivo, advanced synchrotron-based ultrahigh resolution imaging ex-vivo, and a combination of biological, histological and flow cytometry-based cellular and molecular approaches in vitro. Results: We show that systemic blockade of TGFβ activity using a neutralizing mouse monoclonal anti-TGFβ antibody induces a transition from a model of self-contained aortic dilatation to a model of sustained aneurysmal growth culminating in rupture. TGFβ blockade enhances leukocyte infiltration and extracellular matrix degradation, and leads to sustained aneurysmal aortic dilatation, associated with the formation of an intra-luminal thrombus infiltrated with neutrophils, as seen in the human disease. Persistent AAA growth throughout the duration of the experiment is associated with wall disruption without medial dissection, and culminates in fatal aortic wall rupture. Monocyte/macrophage depletion substantially limits AAA severity. Conclusions: Endogenous TGFβ activity is required for the resolution of elastase-induced aortic injury. We expect that this new model will improve our understanding of the pathophysiology of AAA, and will be useful to identify new therapeutic targets.

Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 1, 2015

Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive imm... more Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms linking this pathway to atherosclerosis, as well as a perspective on the risks and benefits of interleukin-17-targeted cytokine therapy in patients at high cardiovascular risk.

Journées annuelles de diabétologie de l'Hôtel-Dieu, 2006

Il existe actuellement au moins deux raisons scientifiques pour que l’obesite soit une maladie in... more Il existe actuellement au moins deux raisons scientifiques pour que l’obesite soit une maladie inflammatoire chronique : l’augmentation des facteurs inflammatoires circulants observee chez les patients obeses et l’identification recente d’une infiltration macrophagique dans le tissu adipeux blanc. Ces observations permettent une revision de la physiopathologie de l’obesite. Il a ete suggere qu’un etat inflammatoire de bas grade est associe aux complications metaboliques et cardiovasculaires de l’obesite. La reduction ponderale est capable d’ameliorer l’etat inflammatoire en diminuant de facon significative les marqueurs inflammatoires circulants et l’infiltration macrophagique du tissu adipeux. Les mecanismes du recrutement des macrophages du tissu adipeux blanc et le role de ce dernier dans les complications de l’obesite ne sont pas encore bien definis. Cet article a pour objectif de mettre a jour les connaissances sur les cytokines inflammatoires et leur role dans l’obesite, et plus particulierement insister sur le role de l’infiltration macrophagique dans le tissu adipeux humain. Les interactions entre les macrophages et les adipocytes seront certainement le sujet d’investigations importantes dans le futur.

Circulation-cardiovascular Genetics, Feb 1, 2012

Background-Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible f... more Background-Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. Methods and Results-We prospectively screened 21 adult STAT3-deficient patients (median age: 26 years; range 17-44 years) for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Conclusions-Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

European Heart Journal, Sep 6, 2012

Aim Interleukin (IL)-17 pathway is being clinically targeted in immune-mediated diseases, most of... more Aim Interleukin (IL)-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction. Methods and results We used data from 981 patients enrolled in the prospective, multicentre French registry of Acute ST elevation, or non-STelevation Myocardial Infarction (Fast-MI, NCT00673036). Serum levels of IL-17 were associated with the risk of all-cause death and recurrent MI at 2 years, with levels of IL-17 below the median indicative of a worse outcome. The impact of IL-17 remained significant after adjustment for known cardiovascular risk factors, C-reactive protein, and treatments including statins: hazard ratio (HR) ¼ 1.40 (1.03-1.91); P ¼ 0.03. IL-17 inhibited mononuclear cell adhesion to endothelium and reduced endothelial vascular cell adhesion molecule (VCAM-1) expression. Patients with low (below the median) IL-17 levels and high (above the median) soluble VCAM-1 (sVCAM-1) levels were at particularly increased risk of death and MI: adjusted HR ¼ 2.22 (1.32-3.75) compared with the high IL-17/low sVCAM-1 group (P ¼ 0.002). Conclusions Low serum levels of IL-17 are associated with a higher risk of major cardiovascular events in Caucasian patients with acute MI. Our results raise possible concern about the use of inhibitors of the IL-17 pathway in clinical settings associated with a high cardiovascular risk. Clinical trials registration: NCT00673036.

Cardiovascular Research, 2018

to overt medial dissection in < 5 days. Similarly, in the aortic root and descending aorta, Tb4KO... more to overt medial dissection in < 5 days. Similarly, in the aortic root and descending aorta, Tb4KO; ApoE-/-mice develop more unstable atherosclerotic plaques, characterised by enhanced contractile-synthetic VSMC switching and dysregulated TGFb/PDGF-BB signalling. In vitro analyses elaborated the endocytic mechanism of Tb4-controlled receptor trafficking and growth factor responses of VSMCs. Ongoing studies seek to evaluate the potential of exogenous Tb4 to protect against disease. Conclusions: We identify a novel regulator of LRP1, the vasculoprotective integrator of TGFb/ PDGF-BB signalling, for maintaining vascular health. Tb4 may emerge as a promising candidate for treatment of vascular disease.

Macrophage-mediated innate immune responses contribute to the initiation, progression and complic... more Macrophage-mediated innate immune responses contribute to the initiation, progression and complications of atherosclerosis. However, the underlying pathways linking activation of macrophages to atherosclerotic plaque develoment are still poorly understood. We hypothesized that activation of caspase recruitment-domain containing protein 9 (CARD9) plays a determinant role in pro-atherogenic responses in macrophages. We showed that global deletion of Card9 in male Apoe−/− mice as well as hematopoietic deletion of Card9 in female Ldlr−/− mice increased atherosclerosis. Card9−/− chimeric animals displayed more inflammatory atherosclerotic plaques and decreased systemic Th17 responses when compared to Card9+/+ chimeric mice. The acceleration of atherosclerosis was also observed in Apoe−/−Rag2−/−Card9−/− mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the pro-atherogenic effect of Card9 deficiency. Card9 deficiency altered macrophage phenotype with inc...

Nature Communications

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular dise... more JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation driv...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2013

Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme that catalizes the degradation of trypt... more Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway, is seen as a major mediator of immune tolerance. Our purpose is to study the role of IDO in an inflammatory disease which is atherosclerosis. We showed that surprisingly the total IDO deletion in LDLr -/- mice ( LDLr -/- IDO -/- ) or in mice reconstituted with IDO -/- bone marrow showed a significant reduction in atherosclerosis (p<0.05). Then, we examined the inflammatory profile of the cells known to express IDO such as macrophages and plasmacytoid dendritic cells (pDC). Interestingly, IDO -/- macrophages or Flt3 ligand-induced bone marrow-derived dendritic cells (mostly plasmacytoid.DC) showed a significant increase of IL-10 expression compared with controls (p<0.05). To examine the role of IL-10 in IDO-mediated effect, we made double knockout- mice IDO -/- IL-10 -/- . Importantly, the resistance of IDO-deficient mice to enhanced atheroscleros...

Archives of Cardiovascular Diseases Supplements

Circulation, 2012

Aim: IL-17 pathway is being clinically targeted in immune-mediated diseases, most of which are as... more Aim: IL-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk.We investigated the relationship between serum level...

Frontiers in Cardiovascular Medicine

IntroductionAmine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and end... more IntroductionAmine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and endothelial cells and enzymatic functions. Given its controversial role in atherogenesis, we proposed to investigate the involvement of AOC3 in the formation of atherosclerotic plaques in ApoE−/−AOC3−/− mice and human coronary arteries.MethodsLesions, contractile markers, and AOC3 were studied in aortic tissues from 15- and 25-week-old mice and different stages of human coronary atherosclerotic arteries by immunohistochemistry (IHC) and/or western blot. Human VSMCs, treated or not with LJP1586, an AOC3 inhibitor, were used to measure differentiation markers by qPCR. AOC3 co-localization with specific cell markers was studied by using confocal microscopy in mice and human samples.ResultsAt 15 weeks old, the absence of AOC3 was associated with increased lesion size, α-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger...

Journal of Clinical Investigation, 2010

Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-... more Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome. Conflict of interest: The authors have declared that no conflict of interest exists.

Circulation, 2016

Necrotic core formation during the development of atherosclerosis is associated with a chronic in... more Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. We hypothesized that sensing of necrotic cells by the C-type lectin receptors CLEC9A plays a determinant role in the inflammatory response of atherosclerosis. Reconstitution of lethally-irradiated Ldlr-/- with bone marrow from CLEC9A-/- mice significantly reduced atherosclerotic lesion size in aortic root (-45%, p=0,0059) after 5 weeks of FAT diet and (-40%, p=0,0017) after 7 weeks of FAT diet, as compared to mice transplanted with wild-type bone marrow-derived cells. However, no effect of CLEC9A was observed after 13 weeks of FAT diet (p=0,4996), suggesting early effect of CLEC9A on atherosclerosis development.The same phenotype was observed in 20-week-old Apoe-/-CLEC9A-/- compared to Apoe-/- mice put on chow diet (-50%, p=0,0022).Interestingly, an increase of IL-10 expression (+60%, p=0,0093) was observed ...