CD40-CD40L: Linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications

Numerous epidemiological studies have consistently demonstrated the strong association between type 2 diabetes mellitus (T2DM) and an increased risk to develop cardiovascular disease. The pathogenesis of T2DM and its complications are characterized by pancreatic, adipose tissue and vascular inflammation. CD40 and CD40L, members of the tumour necrosis factor (receptor) TNF(R) family, are well known for their role in immunity and inflammation. Here we give an overview on the role of CD40-CD40L interactions in the pathogenesis of T2DM with a special focus on pancreatic, adipose tissue and vascular inflammation. In addition, we explore the role of soluble CD40L (sCD40L) as a potential biomarker for the development of cardiovascular disease in T2DM subjects. Finally, the therapeutic potential of CD40-CD40L inhibition in T2DM is highlighted

E3 Ubiquitin Ligases as Immunotherapeutic Target in Atherosclerotic Cardiovascular Disease

Chronic low-grade inflammation drives atherosclerosis and despite optimal pharmacological treatment of classical cardiovascular risk factors, one third of the patients with atherosclerotic cardiovascular disease has elevated inflammatory biomarkers. Additional anti-inflammatory strategies to target this residual inflammatory cardiovascular risk are therefore required. T-cells are a dominant cell type in human atherosclerotic lesions. Modulation of T-cell activation is therefore a potential strategy to target inflammation in atherosclerosis. Ubiquitination is an important regulatory mechanism of T-cell activation and several E3 ubiquitin ligases, including casitas B-lineage lymphoma proto-oncogene B (Cbl-B), itchy homolog (Itch), and gene related to anergy in lymphocytes (GRAIL), function as a natural brake on T-cell activation. In this review we discuss recent insights on the role of Cbl-B, Itch, and GRAIL in atherosclerosis and explore the therapeutic potential of these E3 ubiquitin ligases in cardiovascular medicine

Projet SCIARPA, Formation initiale des architectes, Aide à la réussite Bloc 1, 1er cycle

L’objectif poursuivi par la faculté d’architecture n’est pas la réussite pour tous les apprenants à tout prix, mais plutôt de permettre : • A chaque apprenant de bénéficier des outils mis à sa disposition pour réussir, quels que soient sa situation et ses besoins spécifiques, tout en développant savoirs et compétences ; • Aux encadrants de maintenir le niveau d’exigences en étant partenaires de l’apprenant : trouver l’équilibre entre accompagnement et autonomisation. Le contenu du présent rapport de travail propose de s’adresser à l’apprenant en veillant particulièrement : 1. PRÉVENIR : à l’informer afin qu’il puisse choisir et s’engager en connaissance de cause ; 2. ENSEIGNER : à le placer au centre d’une formation lui donnant accès à toutes les ressources utiles au développement de ses compétences ; 3. DIFFÉRENCIER : à lui fournir un accompagnement personnalisé dans une institution humanisée. La question sous-jacente à la réussite de la 1re année du 1er cycle en formation initiale des architectes est la durée optimale des cycles d’apprentissage tant du point de vue des cours théoriques et/ou pratiques, organisés sur un quadrimestre, qu’en ce qui concerne le cours de projet d’architecture, organisé sur l’année par dérogation au Décret dit « Paysage »

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

Aims: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158. Methods and Results: PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6–8 weeks old male Ldlr–/– mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization. Conclusion: High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis

Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr−/−) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10 mg/kg for 2 weeks enhanced monocyte recruitment to plaques. In follow up, after 6 weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation

Применение оксидно-рутениевых титановых анодов, модифицированных сурьмой для очистки воды

Rationale: Unlike conventional dendritic cells, plasmacytoid DCs (PDC) are poor in antigen presentation and critical for type 1 interferon response. Though proposed to be present in human atherosclerotic lesions, their role in atherosclerosis remains elusive. Objective: To investigate the role of PDC in atherosclerosis. Methods and Results: We show that PDC are scarcely present in human atherosclerotic lesions and almost absent in mouse plaques. Surprisingly, PDC depletion by 120G8 mAb administration was seen to promote plaque T-cell accumulation and exacerbate lesion development and progression in LDLr(-/-) mice. PDC depletion was accompanied by increased CD4(+) T-cell proliferation, interferon-gamma expression by splenic T cells, and plasma interferon-gamma levels. Lymphoid tissue PDC from atherosclerotic mice showed increased indoleamine 2,3-dioxygenase (IDO) expression and IDO blockage abrogated the PDC suppressive effect on T-cell proliferation. Conclusions: Our data reveal a protective role for PDC in atherosclerosis, possibly by dampening T-cell proliferation and activity in peripheral lymphoid tissue, rendering PDC an interesting target for future therapeutic interventions. (Circ Res. 2011;109:1387-1395.

Ablation of CD8 alpha(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice

Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8 alpha(+) DC numbers in spleen and lymph nodes (>80%;P < 0, 001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8 alpha(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8 alpha(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability

The CD40-CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

The CD40-CD40L dyad is an immune checkpoint regulator that promotes both innate and adaptive immune responses and has therefore an essential role in the development of inflammatory diseases, including multiple sclerosis (MS). In MS, CD40 and CD40L are expressed on immune cells present in blood and lymphoid organs, affected resident central nervous system (CNS) cells, and inflammatory cells that have infiltrated the CNS. CD40-CD40L interactions fuel the inflammatory response underlying MS, and both genetic deficiency and antibody-mediated inhibition of the CD40-CD40L dyad reduce disease severity in experimental autoimmune encephalomyelitis (EAE). Both proteins are therefore attractive therapeutic candidates to modulate aberrant inflammatory responses in MS. Here, we discuss the genetic, experimental and clinical studies on the role of CD40 and CD40L interactions in EAE and MS and we explore novel approaches to therapeutically target this dyad to combat neuroinflammatory diseases