Marc Clément

Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease.

Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease

Abdominal aortic aneurysm (AAA) is a major health concern and may be associated with high rates of mortality linked to acute complications. Diagnosis and treatment are, respectively, based on imaging and surgical techniques. Drug-based therapies are still mostly ineffective, which highlight a real unmet need. Major pathophysiological mechanisms leading to aneurysm formation involve inflammatory processes, degradation of the extracellular matrix, and loss of smooth muscle cells. However, the precise cellular and molecular pathways are still poorly understood. Recently, microRNAs have emerged as major intracellular players in a wide range of biological processes, and their stability in extracellular medium within microvesicles has led to propose them as mediators of intercellular crosstalk and as potential biomarkers and therapeutic targets in a variety of disease settings. To date, several studies have been performed to address the involvement of micro-RNAs (miRs) in aneurysm formation and complications. Here, we discuss the roles and implications of miRs in animal models and their relevance to human AAA.

Monocytes and macrophages in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity, and high mortality in the event of aortic rupture. Major advances in open surgical and endovascular repair of AAA have been achieved during the past 2 decades. However, drug-based therapies are still lacking, highlighting a real need for better understanding of the molecular and cellular mechanisms involved in AAA formation and progression. The main pathological features of AAA include extracellular matrix remodelling associated with degeneration and loss of vascular smooth muscle cells and accumulation and activation of inflammatory cells. The inflammatory process has a crucial role in AAA and substantially influences many determinants of aortic wall remodelling. In this Review, we focus specifically on the involvement of monocytes and macrophages, summarizing current knowledge on the roles, origin, and functions of these cells in AAA development and its complications. Furthermore, we show and propose that distinct monocyte and macrophage subsets have critical and differential roles in initiation, progression, and healing of the aneurysmal process. On the basis of experimental and clinical studies, we review potential translational applications to detect, assess, and image macrophage subsets in AAA, and discuss the relevance of these applications for clinical practice.

Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response

Background: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation. Methods: We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro and on the development of atherosclerosis using low-density lipoprotein receptor–deficient (Ldlr−/−) mice in vivo. Results: We show that Clec4e is expressed within human and mouse atherosclerotic lesions and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum stress response, leading to the induction of proinflammatory mediators and growth factors. Chop and Ire1a deficiencies significantly limit Clec4e-dependent effects, whereas Atf3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of Ldlr−/− mice with Clec4e−/− bone marrow reduces lipid accumulation, endoplasmic reticulum stress, and macrophage inflammation and proliferation within the developing arterial lesions and significantly limits atherosclerosis. Conclusions: Our results identify a nonredundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis and suggest that it may play similar roles in other chronic inflammatory diseases.

Type-2 innate lymphoid cells control the development of atherosclerosis in mice.

Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr−/− mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5−/− or Il13−/− ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.

The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice

Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8&agr;+ subset of dendritic cells (CD8&agr;+ DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. Objective: We sought to address the impact of total, bone marrow–restricted, or CD8&agr;+ DC–restricted deletion of DNGR-1 on atherosclerosis development. Methods and Results: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)–deficient mice (Apoe−/−) and bone marrow–restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)–deficient mice (Ldlr−/−) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow–derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8&agr;+ DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. Conclusions: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.

Diabetes and aortic aneurysm: current state of the art

Abstract Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture. The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, highlighting an unmet need for clinical practice. Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia. Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors. Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA. A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease. Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm. Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation.