Crossroad between Inflammation, Iron and Lipids in Atherogenesis

Atherosclerosis (ATH) is recognized as a chronic inflammatory condition and it is the leading cause of cardiovascular disease. The process of atherogenesis is characterized by the accumulation and oxidation of LDL (oxLDL) in the vessel wall and subsequent infiltration and activation of immune cells, particularly monocytes in an earlier stage and, later on, lymphocytes. The infiltrated monocytes differentiate into macrophages which then could differentiate into foam cells as a consequence of oxLDL uptake [1]. The recruitment of immune cells to the site of ATH lesion contributes to a local pro-inflammatory state that will promote the development of the atheroma plaque and progression of the disease. However, the exact mechanisms involved in this process are not fully understood. One hypothesis is the contribution of oxidative stress mediated by metals such as iron [2]. Previous authors have shown high iron content in foam cells and also accumulation of hemoglobin and ferritin in the areas rich in foam cells [3]. Herein, we investigate a possible mechanism for cellular iron accumulation by testing the effect of pro-inflammatory as well as pro-atherogenic stimuli in the expression of proteins involved in iron efflux in macrophages.This work was supported by National Institute of Health Doutor Ricardo Jorge, I.P, INSERM (Institut National de la Santé et de la Recherche Médicale), CNRS (Centre National de la Recherche Scientifique), ANR (Agence Nationale de la Recherche, France; ANR- 08- GENO-000) , Fundação para a Ciência e Tecnologia (Grant SFRH/BD/48671/2008) and BioFIG (Center for Biodiversity, Functional and Integrative Genomics)

Place et contrat institutionnels des discussions à visée philosophique pratiquées à l'école primaire

International audienceL'article interroge la place des pratiques effectives de discussion à visée philosophique à l'école primaire. Sur la base de quinze années d'études des discussions, et à partir d'échanges enseignants-élèves retranscrits, l'article montre en quoi ces dispositifs permettent de travailler un contrat de communication à la fois inédit et clairement situé parmi les oraux scolaires. La réflexion des sciences humaines et sociales sur ce genre de discussions scolaires comme la question épineuse d'une institutionnalisation, en termes d'avantage vs désavantage au regard des pratiques actuelles, sont avancées

Les rafts , radeaux lipidiques membranaires, participent à la régulation du transporteur de fer, la ferroportine, dans les macrophages

Le fer est un élément vital mais en excès il peut devenir toxique pour l organisme. Une régulation fine de son adsorption (au niveau du duodénum) et de son recyclage (au niveau des macrophages tissulaires) est donc indispensable. Cette régulation implique l hepcidine, un peptide produit majoritairement par les hépatocytes, et qui induit l endocytose et la dégradation du seul exportateur de fer connu chez les mammifères, la ferroportine. Nous avons étudié, dans les macrophages, la localisation subcellulaire de la ferroportine, sa régulation et nous avons recherché des partenaires protéiques fonctionnels ou régulateurs potentiels de cette protéine. Nous avons montré que ce transporteur est localisé dans des radeaux lipidiques (rafts) à la surface des macrophages. De plus, la désorganisation des rafts induit une diminution de la dégradation de la ferroportine par l hepcidine. Le transport de fer au niveau cellulaire semble impliquer une ferroxidase, la céruloplasmine. Nos macrophages en culture expriment une céruloplasmine cytosolique et une céruloplasmine membranaire liée à la membrane par une ancre GPI (glycosylphosphatidylinositol). Après un traitement au fer, la ferroportine et les deux formes de céruloplasmine sont surexprimées avec une céruloplasmine membranaire localisée dans des rafts de même densité que ceux de la ferroportine. Ensemble, nos observations soulignent l importance fonctionnelle des rafts dans le recyclage du fer macrophagique. Une approche protéomique des fractions rafts contenant la ferroportine nous suggèrent déjà certains acteurs moléculaires impliqués dans l activité et la régulation de la ferroportine macrophagique.ORSAY-PARIS 11-BU Sciences (914712101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

The effect of pro-inflammatory conditions on iron homeostasis and atherogenesis

This work was supported by National Institute of Health Dr Ricardo Jorge, I.P, INSERM (Institut National de la Santé et de la Recherche Médicale), CNRS (Centre National de la Recherche Scientifique), ANR (Agence Nationale de la Recherche, France; ANR- 08-GENO-000) , Fundação para a Ciência e Tecnologia (Grant SFRH/BD/48671/2008) and BioFIG (B Center for Biodiversity, Functional and Integrative Genomics).Atherosclerosis (ATH) is recognized as a chronic inflammatory condition and it is the leading cause of cardiovascular disease. Atherogenesis is characterized by the accumulation and oxidation of LDL (oxLDL) in the vessel wall and subsequent infiltration, activation of lymphocytes and monocytes, these later ones differentiating into macrophages and subsequently into foam cells. The recruitment of immune cells to the site of lesion contributes to a local pro-inflammatory state that will promote the development of the atheroma plaque and progression of the disease. However, the exact mechanisms involved in this process are not fully understood. One hypothesis is the contribution of oxidative stress mediated by metals such as iron. Previous authors have shown high iron content in foam cells and also accumulation of hemoglobin and ferritin in the areas rich in foam cells. Herein, we investigate a possible pathway for cellular iron accumulation by testing the effect of pro-inflammatory as well as pro-atherogenic stimuli in the expression of proteins involved in iron efflux from macrophages. Mouse bone marrow-derived macrophages (BMDM) were treated with LPS, iron or/and oxLDL. The expression of ferroportin (Fpn, iron exporter), beta-amyloid precursor protein (APP, ferroxidase), ceruloplasmin (Cp, ferroxidase) and hemoxygenase-1 (HO-1, heme catabolism) were analyzed by western blot of subcellular fractions (cytosol, membrane and lipid raft fractions). Oil Red O staining was used to follow foam cell differentiation by oxLDL treatment. APP and HO-1 were shown to be upregulated by both iron and LPS, being recruited to lipid rafts enriched fractions in BMDM. Fpn, present also in lipid rafts, was upregulated by iron and downregulated by LPS confirming our previous observations. Such modulation of proteins involved in iron efflux by inflammatory stimuli could also contribute to disruption of iron metabolism in plaque macrophages. In addition, foam cell differentiation of BMDM by oxLDL was accelerated in the presence of iron. These observations suggest that iron in plaque could be a pro-atherogenic factor. Moreover, effect of oxLDL expression and localization of iron-related proteins on lipid raft microdomains may constitute an important pathway for iron efflux disruption in the plaque environment and is under investigation

Process integration of boron BSF by CVD technique on large surface in bifacial solar cell process flow

International audienc

Iron- and Hepcidin-Independent Downregulation of the Iron Exporter Ferroportin in Macrophages during Salmonella Infection

Retention of iron in tissue macrophages via upregulation of hepcidin (HAMP) and downregulation of the iron exporter ferroportin (FPN) is thought to participate in the establishment of anemia of inflammation after infection. However, an upregulation of FPN has been proposed to limit macrophages iron access to intracellular pathogens. Therefore, we studied the iron homeostasis and in particular the regulation of FPN after infection with Salmonella enterica serovar Typhimurium in mice presenting tissue macrophages with high iron (AcB61), basal iron (A/J and wild-type mice), or low iron (Hamp knock out, Hamp−/−) levels. The presence of iron in AcB61 macrophages due to extravascular hemolysis and strong erythrophagocytosis activity favored the proliferation of Salmonella in the spleen and liver with a concomitant decrease of FPN protein expression. Despite systemic iron overload, no or slight increase in Salmonella burden was observed in Hamp−/− mice compared to controls. Importantly, FPN expression at both mRNA and protein levels was strongly decreased during Salmonella infection in Hamp−/− mice. The repression of Fpn mRNA was also observed in Salmonella-infected cultured macrophages. In addition, the downregulation of FPN was associated with decreased iron stores in both the liver and spleen in infected mice. Our findings show that during Salmonella infection, FPN is repressed through an iron and hepcidin-independent mechanism. Such regulation likely provides the cellular iron indispensable for the growth of Salmonella inside the macrophages

Iron- and Hepcidin-Independent Downregulation of the Iron Exporter Ferroportin in Macrophages during Salmonella Infection

Retention of iron in tissue macrophages via upregulation of hepcidin (HAMP) and downregulation of the iron exporter ferroportin (FPN) is thought to participate in the establishment of anemia of inflammation after infection. However, an upregulation of FPN has been proposed to limit macrophages iron access to intracellular pathogens. Therefore, we studied the iron homeostasis and in particular the regulation of FPN after infection with Salmonella enterica serovar Typhimurium in mice presenting tissue macrophages with high iron (AcB61), basal iron (A/J and wild-type mice), or low iron (Hamp knock out, Hamp(-/-)) levels. The presence of iron in AcB61 macrophages due to extravascular hemolysis and strong erythrophagocytosis activity favored the proliferation of Salmonella in the spleen and liver with a concomitant decrease of FPN protein expression. Despite systemic iron overload, no or slight increase in Salmonella burden was observed in Hamp(-/-) mice compared to controls. Importantly, FPN expression at both mRNA and protein levels was strongly decreased during Salmonella infection in Hamp(-/-) mice. The repression of Fpn mRNA was also observed in Salmonella-infected cultured macrophages. In addition, the downregulation of FPN was associated with decreased iron stores in both the liver and spleen in infected mice. Our findings show that during Salmonella infection, FPN is repressed through an iron and hepcidin-independent mechanism. Such regulation likely provides the cellular iron indispensable for the growth of Salmonella inside the macrophages

Paroles de philosophes en herbe

Cet ouvrage est le fruit d'un dialogue entamé par une vingtaine de chercheurs d'horizons géographiques différents (Belgique, Canada, France et Suisse), et de domaines de recherche variés (philosophie, sciences du langage, ergonomie, psychologie, didactique…), lors d'un séminaire d'automne organisé en octobre 2015 par le laboratoire LiDILEM : « Regards croisés de philosophes, linguistes, didacticiens, psychologues, ergonomes … sur une discussion à visée philosophique : « pourquoi on dit : c'est pas juste » ». La démarche de séminaire était de proposer aux chercheurs d'analyser une Discussion à Visée Démocratique et Philosophique (DVDP) animée par Michel TOZZI auprès d'un public de CM2 lors des journées mondiales de la philosophie organisées par l'UNESCO en novembre 2014. Un appel à contribution a donc été lancé auprès de chercheurs de différents champs disciplinaires : philosophie, psychologie, sciences de l'éducation, sciences du langage… À l'issue de ce séminaire M. Tozzi revenant sur les modèles et les analyses présentés, a posé un certain nombre de pistes de recherche formulant un ensemble de questions et suggérant « que chacun explicite en quoi le modèle qu'il convoque lui semble pertinent pour répondre à telle ou telle question… » ce qui a donné les grandes lignes de cette publication collective. Nous avons tenu à ce que le corpus soit présenté dans la partie introductive de l'ouvrage afin que le lecteur (praticien ou formateur) puisse confronter son regard aux analyses présentées. Nous mettons également à disposition de tout chercheur qui souhaite faire une analyse de ce corpus plusieurs transcriptions de cette séance (format texte, mais aussi balisé XML - avec ELAN© notamment) ainsi que de la vidéo