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Gui, Philippe. "Caractérisation de la migration trans-tissulaire des macrophages." Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2612/.
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L'infiltration de macrophages dans les tumeurs est associée à un mauvais pronostic. Le contrôle de leur migration trans-tissulaire représente donc un enjeu thérapeutique important. Ma thèse a consisté à identifier les mécanismes impliqués dans cette migration. Grâce à des approches d'observation directe du comportement migratoire des cellules dans des tissus vivants (microscopie intravitale et explants tissulaires ex vivo), je montre que les macrophages in vivo adoptent un mode de migration distinct selon le tissu. Dans un fibrosarcome (tissu dense), ils ont une migration de type mésenchymateux (dépendante des protéases), tandis que dans le derme sain adjacent, ils ont une migration de type amiboïde (indépendante des protéases). De plus, j'ai identifié une protéine, p27kip1, impliquée dans la migration mésenchymateuse. Ainsi, en montrant que la migration mésenchymateuse des macrophages existe in vivo, notamment dans les tumeurs, elle pourra devenir une cible thérapeutique prometteuseThe infiltration of macrophages inside tumors is associated with a poor prognosis. Therefore, the specific control of their trans-tissular migration represents an important therapeutic challenge. My thesis has consisted in identifying the mechanisms involved in this migration. Using approaches allowing the observation of the migration behavior of cells directly inside living tissues (intravital microscopy and ex vivo tissue explants), I show that macrophages adopt a distinct migration mode in vivo depending on the tissue. In a fibrosarcoma (dense tissue), they use a mesenchymal-like migration (protease-dependent), whereas in the healthy surrounding derma, they use an amoeboid-like migration (protease-independent). Moreover, I identified a protein, p27kip1, involved in mesenchymal migration. In conclusion, by showing that the mesenchymal migration of macrophages exists in vivo, particularly in tumors, it could become a promising therapeutic target
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Van, Goethem Emeline. "Caractérisation de la migration trans-matricielle des phagocytes humains." Toulouse 3, 2010. http://thesesups.ups-tlse.fr/1061/.
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Le recrutement des macrophages et neutrophiles sur un site infecté ou enflammé est une étape clé de la réponse immunitaire innée. Cependant, dans certaines maladies (maladies inflammatoires chroniques, cancers. . . ), le recrutement chronique et massif des macrophages participe à la progression de la pathologie. In vivo, les phagocytes migrent essentiellement au sein d'un environnement tri-dimensionnel (3D). Si rien n'était connu sur la migration 3D des macrophages, celle des cellules tumorales, bien documentée, avait permis de montrer qu'elle fait appel à des mécanismes très différents de la migration 2D et de définir deux modes principaux de migration : le mode mésenchymal, dépendant de la dégradation de la matrice extra-cellulaire (MEC) par les protéases et le mode amiboide, indépendant de cette dégradation. L'objectif de ma thèse a été de caractériser le mode migratoire 3D des macrophages humains dans un modèle d'étude simple in vitro permettant de comparer la migration dans des matrices de compositions, d'architectures et de propriétés visco-élastiques différentes. J'ai ainsi pu montrer que 1) les macrophages humains sont capables d'adopter les deux modes migratoires décrits à ce jour, 2) le choix du mode migratoire est dicté par l'architecture de la matrice rencontrée, 3) les macrophages utilisent le mode mésenchymal pour traverser les MEC les moins poreuses notamment via la mise en place de structures dégradatives : les podosomes 3D. L'évaluation des modes migratoires des différentes sous populations de macrophages et des autres phagocytes humains (monocytes, neutrophiles et cellules dendritiques) a fait suite à ce travail et est encore en cours d'expérimentationRecruitment of macrophages and neutrophils to the inflamed or infected site is a critical step of innate immune response. However, in some diseases (chronic inflammatory disorders, cancers. . . ), the recruitment becomes chronic and massive, and participates in pathology progression. In vivo, phagocytes are mainly migrating within a three-dimensional (3D) environment. If nothing was known about 3D migration of macrophages, the one of tumor cells is well documented. It allowed to establish that 2D migration and 3D migration do not require the same mechanisms and to identify two main migration modes: the mesenchymal mode, dependent on extra-cellular matrix (ECM) degradation by proteases and the amoeboid mode, independent on that degradation. The aim of my PhD was to characterize the 3D migratory behaviour of human macrophages using a simple in vitro model that allowed us to compare migration within matrices of different composition, architecture and visco-elastic properties. I was thus able to show that 1) human macrophages are able to adopt the two migration modes described so far, 2) the choice of migratory mode is dictated by the architecture of the matrix encountered, 3) macrophages are using the mesenchymal mode to migrate within the least porous ECM, through the formation of degradative structures: the 3D podosomes. Following this work, 3D migration of different macrophage sub-populations and of other human leukocytes: monocytes, neutrophils and dendritic cells has been evaluated and this study is still on going
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Stamps, Stacy Leanne. "Determination of a catalytic mechanism for the enzymatic activity of macrophage migration inhibitory factor /." Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
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Murray, Megan. "Metalloproteinase expression in bone marrow-derived macrophages : roles in cell migration." Thesis, University of East Anglia, 2010. https://ueaeprints.uea.ac.uk/20512/.
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Desvignes, Emma. "Dispositifs fluidiques 3D pour l'étude de la migration cellulaire des macrophages." Thesis, Toulouse, INSA, 2018. http://www.theses.fr/2018ISAT0046.
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Au cours des deux dernières décennies, des études ont été réalisée pour mesurer les forces mécaniques exercées par des cellules vivantes sur leur environnement. Cela a conduit au développement de diverses techniques ingénieuses qui ont principalement été réalisées pour comprendre la façon dont les cellules exercent des forces pendant leur migration sur des substrats bidimensionnels (2D). Cependant, in vivo, les cellules migrent à travers des environnements tridimensionnels (3D) et les mécanismes utilisés pour migrer en 3D diffèrent significativement de ceux de la migration 2D. A titre d'exemple, les cellules confinées en 3D rencontrant des constrictions ont besoin de déformer leur noyau, leur organelle le plus grand et le plus rigide. En 2D, les noyaux ne sont pas des facteurs limitants pour la migration. Il est donc nécessaire de développer des outils pour comprendre comment les cellules migrent en 3D. En particulier, des études doivent être menées pour déterminer comment les cellules appliquent des forces en fonction du niveau de confinement auquel elles se trouvent confrontées. Pour répondre à cette question difficile, nous avons développé deux types de micro-dispositifs. Tout d'abord, nous avons conçu et fabriqué un dispositif de microfluidique pour étudier les forces générées par les cellules pendant une migration confinée. Ce dispositif est constitué de microcanaux de dimensions contrôlées équipés de micropiliers, servant de capteurs de forces .Ces capteurs de forces présentent une sensibilité de l’ordre de 70 pN. Nous avons ensuite introduit dans le dispositif des macrophages humains, cellules du système immunitaire, à l'intérieur du dispositif et évalué la flexion des micropiliers engendrée par les forces cellulaires appliquées lors de leur migration. Grâce au développement d’un algorithme permettant l’analyse des images, nous avons pu évaluer les forces générées dans différentes zones cellulaires et révéler que les cellules redirigent les forces de pression de l'intérieur vers l'extérieur lorsque le degré de confinement augmente. Cette observation suggère un mode de migration très spécifique lié au confinement spatial qui est basé sur l’appui sans adhésion sur les obstacles de l’environnement. Dans un deuxième temps nous avons fabriqué des réseaux tri-dimensionnels obtenus par une méthode de lithographie bi-photonique 3D. Les motifs de ces réseaux possèdent des dimensions caractéristiques de l'échelle cellulaire (1-10 μm) et sont composés de poutres suspendues qui peuvent être courbés par les cellules vivantes qui migrent au sein du treillis tri-dimensionnel. En enregistrant une séquence vidéo des déformations de l'échafaudage, nous pouvons étudier l'activité mécanique de la cellule dans l'espace et le temps pendant sa migration 3D. Nos résultats montrent que les macrophages sont capables de pénétrer dans des réseaux de géométrie cubique lorsque la période du réseau est supérieure à 5 μm et que le support de migration lui-même peut être utilisé comme capteur pour mesurer les forces exercées par les cellules. Grâce à la mesure de la rigidité du matériau constituant le treillis 3D et des modélisations de la déformation élastique de la structure 3D, nous avons pu évaluer que la contrainte mécanique globale qu’exerce un macrophage sur son microenvironnement est de l’ordre de 500 kPa. Grâce à la combinaison de la microfabrication, l'imagerie cellulaire et l'analyse automatisée des images, nous sommes parvenus à quantifier les efforts mécaniques cellulaires mis en jeu lors de la migration de macrophages humains au sein d’environnements confinés et nous mettons ainsi en lumière la mécanique spécifique des cellules migrant en 3DOver the past two decades, studies have been conducted to measure the mechanical forces exerted by living cells on their environment. This has led to the development of a variety of ingenious techniques that have been primarily developed to understand how cells exert forces during their migration on 2D substrates. However, in vivo, cells migrate through three-dimensional (3D) environments and the mechanisms used to migrate in 3D differ significantly from those of 2D migration. For example, confined cells in 3D encountering constrictions need to deform their nucleus, their largest and most rigid organelle. In 2D, kernels are not limiting factors for migration. It is therefore necessary to develop tools to understand how cells migrate in 3D. In particular, studies need to be conducted to determine how cells apply forces based on the level of containment they encounter. To answer this difficult question, we have developed two types of micro-devices. First, we designed and manufactured a microfluidic device to study the forces generated by cells during a confined migration. This device consists of microchannels of controlled dimensions equipped with micropiliers, serving as force sensors. These force sensors have a sensitivity of the order of 70 pN. We then introduced into the device human macrophages, cells of the immune system, inside the device and evaluated the bending of micropiliers generated by the cellular forces applied during their migration. Through the development of an algorithm for image analysis, we have been able to evaluate the forces generated in different cell areas and reveal that cells are redirecting pressure forces from the inside to the outside as the degree of containment increases. This observation suggests a very specific mode of migration related to spatial confinement that is based on the support without adhesion on the obstacles of the environment. In a second time we made three-dimensional networks obtained by a 3D bi-photonic lithography method. Les motifs de ces réseaux possèdent des dimensions caractéristiques de l'échelle cellulaire (1-10 μm) et sont composés de poutres suspendues qui peuvent être courbés par les cellules vivantes qui migrent au sein du treillis tri-dimensionnel. En enregistrant une séquence vidéo des déformations de l'échafaudage, nous pouvons étudier l'activité mécanique de la cellule dans l'espace et le temps pendant sa migration 3D. Nos résultats montrent que les macrophages sont capables de pénétrer dans des réseaux de géométrie cubique lorsque la période du réseau est supérieure à 5 μm et que le support de migration lui-même peut être utilisé comme capteur pour mesurer les forces exercées par les cellules. Grâce à la mesure de la rigidité du matériau constituant le treillis 3D et des modélisations de la déformation élastique de la structure 3D, nous avons pu évaluer que la contrainte mécanique globale qu’exerce un macrophage sur son microenvironnement est de l’ordre de 500 kPa. Grâce à la combinaison de la microfabrication, l'imagerie cellulaire et l'analyse automatisée des images, nous sommes parvenus à quantifier les efforts mécaniques cellulaires mis en jeu lors de la migration de macrophages humains au sein d’environnements confinés et nous mettons ainsi en lumière la mécanique spécifique des cellules migrant en 3D
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Prieto-Lafuente, Lidia. "Macrophage-migration Inhibitory Factor (MIF) homologues in the host-parasite interaction." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/3458.
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The ability of filarial parasites to persist in an immunological competent host, has led to the suggestion that they have evolved specific measures to counter immune defences. Filarial nematodes produce and secrete excretory-secretory (ES) products, some of which have been described to have a potential role in immune evasion. As part of these ES products, two homologues of the mammalian cytokine macrophage-migration inhibitory factor (MIF) have been described from the filarial nematode Brugia malayi, Bm-MIF-1 and Bm-MIF-2. Mammalian MIF is a widely distributed protein constitutively expressed in many immune and non-immune cell types. Although firstly characterised by its ability to stop migration of peritoneal macrophages, it has now been shown to play an important role during different inflammation processes. The main aim of this study is to elucidate the role of Brugia MIF homologues and their relation with the mammalian cytokine. This thesis studies the effect of both filarial and host MIF homologues on two major immune cell types, macrophages and dendritic cells (DC). We found that both Brugia and mouse-MIF synergise with IL-4 to activate macrophages to an alternative phenotype, by enhancing expression of IL-4-induced alternative activation markers Arginase-1, Ym-1 and the macrophage Mannose Receptor. MIF also synergises with IL-4 to render macrophages suppressive, an important outcome during filarial infection. Additionally we found that MIF homologues induce IL-4Ra expression, suggesting a mechanism by which MIF enhances IL-4 activation. We showed that filarial and mouse MIF homologues differ in their capacity to activate bone marrow-derived immature dendritic cells. Mouse-MIF up-regulates MHC-II and CD40 expression and induces pro-inflammatory cytokine production after overnight treatment. On the other hand Bm-MIF-2 induces low levels of cytokine production but does not up-regulate activation markers, and Bm-MIF-1 failed to activate DC. Furthermore, we demonstrate that filarial MIF homologues impair DC differentiation from bone marrow precursors. While bone marrow cells cultured in the presence of GM-CSF, with or without mouse-MIF, differentiate into CD11c+ DC, addition of Bm-MIF-2 to the culture media impairs differentiation arresting the cells in an undifferentiated phenotype characterised by the expression of myeloid and granulocyte markers CD11b and GR1. Finally, using an in vivo model where we implant Brugia malayi parasites in the peritoneal cavity of mice, we observed that host MIF does not play an essential role in the activation of macrophages by adult parasites as macrophages form MIF deficient mice present the same phenotype as their wild type counterparts.
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Smolders, Sophie. "La migration des microglies et les molécules adhésives au cours du développement embryonnaire du cerveau." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066533/document.
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Les microglies sont des cellules hématogène mais prennent place dans le système nerveux central (SNC) au cours du développement embryonnaire pour constituer la population résidente des cellules immunitaires. Elles sont les médiateurs crucials du bon développement et de l'entretien des réseaux de neurones dans le SNC. De nombreux aspects de la physiologie microgliale et les mécanismes qui sous-tendent leurs fonctions au cours du développement embryonnaire du cerveau sont encore largement méconnues. Cette thèse de doctorat porte sur la migration des cellules microgliales au cours du développement embryonnaire du cortex et elle débouche sur trois grandes conclusions. (1) Les cellules microgliales embryonnaires in situ sont très dynamiques et adaptent leur phénotype à leur environnement local. (2) La vitesse de migration des microglies ex vivo dépend des intégrines beta1 qui exercent des fonctions à la fois inhibitrices et promotrices sur la migration selon l'âge embryonnaire. (3) Les microglies jouent probablement un rôle dans l'étiologie des troubles du développement neurologique, mais il faudrait que les futures recherches se concentrent sur le dysfonctionnement des microglies plutôt que sur leur activation immunitaire classiqueMicroglia are blood-borne cells but take up residence in the central nervous system (CNS) during embryonic development to constitute the resident pool of immune cells. They are crucial mediators of the healthy development and maintenance of neural networks in the CNS. Many aspects of the physiology of microglia and the mechanisms underpinning their tasks during embryonic brain development are still unresolved. This doctoral dissertation focuses on migration of microglial cells during embryonic cortical development. All together, this dissertation brings forwards three major conclusions. (1) In situ embryonic microglia are highly dynamic cells that adapt their phenotype to their local environment. (2) Microglial migration speed ex vivo is dependent on β1 integrins that exert both migration promoting and inhibiting functions which are age-specifically regulated. (3) Microglia likely play a role in the etiology of neurodevelopmental disorders, but further research should focus on microglia dysfunction rather than classical microglial immune activation
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Souriant, Shanti. "Rôle des macrophages au cours de l'infection par le VIH-1 et dans un contexte de co-infection avec Mycobacterium tuberculosis." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30209.
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Les macrophages sont une cible cellulaire du VIH-1, et jouent un rôle important dans la pathogenèse virale. Au cours de ma thèse, je me suis intéressée au rôle des macrophages dans la pathogenèse du VIH-1, mais aussi au cours de la co-infection avec Mycobacterium tuberculosis (Mtb), l'agent étiologique de la tuberculose. J'ai tout d'abord participé à une étude mettant en évidence que l'infection par le VIH-1 reprogramme la migration des macrophages, favorisant notamment le mode migratoire protéolytique. Cet effet est médié par l'interaction de la protéine virale Nef avec les protéines de l'hôte Hck et WASP, ce qui conduit à une modification de l'organisation et de la fonction des podosomes, structures impliquées dans la dégradation de la matrice extracellulaire et la migration dépendante des protéases. La meilleure capacité à migrer des macrophages infectés par le VIH-1 in vitro se traduit in vivo par une augmentation du recrutement des macrophages dans différents tissus de souris transgéniques qui expriment la protéine Nef. Ces travaux ont ainsi révélé un nouveau mécanisme par lequel le VIH-1 dissémine dans les tissus, via l'action de Nef dans les macrophages. L'association fréquente du VIH-1 avec Mtb complique le problème de santé publique posé par l'infection virale. En effet, Mtb aggrave la pathogenèse du VIH-1 chez les patients co-infectés. L'étude des mécanismes impliqués et le rôle des macrophages dans ce phénomène constituent les objectifs principaux de ma thèse. J'ai révélé que les macrophages infectés par Mtb génèrent un microenvironnement qui active les macrophages voisins vers un programme de polarisation anti-inflammatoire dit M(IL-10). J'ai mis en évidence que ces macrophages M(IL-10) sont particulièrement efficaces pour la production de VIH-1. J'ai démontré que le microenvironnement associé à la tuberculose entraîne la formation de nanotubes entre les macrophages, grâce à l'activation de la signalisation cellulaire médiée par l'axe IL-10/STAT3. Ces nanotubes, qui favorisent le transfert du virus d'un macrophage à un autre, sont à l'origine de la spectaculaire production de VIH-1 par les macrophages. Nous avons également constaté que ces cellules M(IL-10) s'accumulent dans la circulation sanguine des patients co-infectés ainsi que dans les poumons de primates non-humains co-infectés. Dans l'ensemble, mes travaux identifient les nanotubes comme des acteurs clés dans l'aggravation de la pathogenèse du VIH-1 lors de la co-infection avec Mtb. Ainsi, les nanotubes et la voie de signalisation IL-10/STAT3 pourraient représenter des cibles pour développer de nouvelles thérapies de lutte contre la comorbidité VIH/Mtb. Les résultats obtenus lors de ma thèse contribuent à une meilleure compréhension du rôle des macrophages dans la pathogenèse et la dissémination du VIH-1 dans un contexte de mono-infection, ou lors d'une co-infection avec MtbMacrophages are both crucial host effector cells for HIV-1 and important leukocytes involved in viral pathogenesis. For my doctoral thesis, I was interested in further characterizing the role of macrophages in HIV-1 pathogenesis, and during co-infection with Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis (TB). I first participated in a study that provided evidence that HIV-1 infection reprograms the migration of macrophages, particularly by triggering the protease-dependent migration mode. This effect was mediated by the interaction of the viral protein Nef with the host proteins Hck and WASP, which leads to modification in the organization and proteolytic activity of podosomes, important structures for protease-dependent migration. The higher migration capacity of HIV-1-infected macrophages translated in vivo by an increase in the recruitment of macrophages in several tissues of Nef-transgenic mice. This work revealed a novel mechanistic understanding of how HIV-1 infection drives macrophages into tissues, contributing to viral dissemination and possibly creating a hidden cellular reservoir of virus. Worsening this public health issue posed by the HIV-1 epidemic is the frequent association of the virus with Mtb. Indeed, Mtb aggravates HIV-1 pathogenesis in co-infected individuals. Yet, the mechanisms involved in this process are still poorly understood, including the contribution of macrophages. To investigate how Mtb exacerbates the HIV-1 infection in human macrophages was the main focus of my thesis. First, I revealed that Mtb-infected macrophages generate a microenvironment that drives bystander macrophages towards phenotypic and functional features of the so-called M(IL-10) anti-inflammatory program. I found that these M(IL-10) macrophages are highly efficient for HIV-1 production. I demonstrated that the TB-associated microenvironment induces the formation of macrophage-to-macrophage connecting tunneling nanotubes (TNTs) through the IL- 10/STAT3 axis, a phenomenon that is responsible for the dramatic increase of HIV-1 production in M(IL-10) macrophages. Moreover, I provided evidence that M(IL-10) cells are expanded in the peripheral blood of co-infected patients and accumulate in the lungs of co-infected non-human primates. Altogether, this central part of my PhD thesis sheds light to TNTs as key players in the aggravation of HIV-1 pathogenesis in human macrophages during co-infection with Mtb. Thus, this cellular mechanism (together with the IL- 10/STAT3 axis) could represent an unexpected target to develop novel therapeutics against AIDS/TB co-morbidity. Collectively, the results obtained during my thesis contribute to a better understanding of the role of macrophages during HIV-1 pathogenesis and their ability to disseminate the virus in a mono-infection context, or during co-infection with Mtb
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Veillat, Véronique. "Régulation et mécanismes d'action du facteur inhibiteur de la migration des macrophages (MIF) dans l'endométriose." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27082/27082.pdf.
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Barnes, Mark Aaron Jr. "MACROPHAGE MIGRATION INHIBITORY FACTOR AND LIVER DISEASE: THE ROLE OF MIF IN ALCOHOL-INDUCED LIVER INJURY AND CARBON TETRACHLORIDE (CCI4)-INDUCED LIVER FIBROSIS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396429556.
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Guiet, Romain. "Étude des mécanismes cellulaires et moléculaires de la migration des macrophages humains dans des environnements en trois dimensions." Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1487/.
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L'infiltration tissulaire des macrophages est un facteur aggravant dans de nombreuses pathologies telles que les maladies inflammatoires chroniques ou le cancer. Les macrophages qui infiltrent les tumeurs de façon continue sont appelés macrophages associés aux tumeurs (TAMs). Ils favorisent la croissance tumorale, l'angiogenèse, l'invasion tumorale et la formation de métastases. L'inhibition de l'infiltration des macrophages est donc devenue une évidence thérapeutique. Récemment, l'équipe a démontré que les macrophages utilisent le mode migratoire amiboïde (dépendant de ROCK) ou mésenchymal (dépendant des protéases) selon l'architecture de la matrice extracellulaire (MEC) en trois-dimensions (3D) qu'ils traversent. De plus, l'étude du mode migratoire mésenchymal a montré qu'il est dépendant de Hck (une tyrosine kinase spécifique des phagocytes) et de sa capacité à réorganiser les podosomes en rosettes (structures riches en actine dégradant la MEC). Mon projet de thèse s'est articulé autour de deux axes de recherche : 1) l'identification des substrats de Hck et la caractérisation de leur rôle dans l'organisation des podosomes et la migration 3D des macrophages, et 2) l'étude de la migration 3D des monocytes/macrophages primaires humains dans un modèle mimant le microenvironnement tumoral : les sphéroïdes tumoraux. Par une approche protéomique j'ai identifié des partenaires et substrats potentiels de Hck dont la Filamine A (FLNa), une protéine assurant notamment la liaison entre le cytosquelette d'actine et les intégrines. En utilisant différents outils (protéines recombinantes, anticorps, shRNA. . . ) j'ai montré que : 1) Hck phosphoryle la FLNa in vitro, 2) la FLNa est associée aux podosomes et est nécessaire à leur organisation en rosettes sous le contrôle de Hck, 3) les podosomes des cellules déficientes en Flna ont une durée de vie plus courte, et 4) l'expression de la FLNa est nécessaire à la migration mésenchymale, mais pas à la migration amiboïde des macrophages dans une MEC en 3D. Ainsi la FLNa est impliquée dans la formation et à la stabilisation des podosomes, à leur organisation en rosettes, la migration mésenchymale des macrophages et pourrait se situer dans la voie de signalisation de Hck. En parallèle, j'ai mis au point un modèle de sphéroïdes tumoraux qui m'a permis de montrer que l'infiltration des monocytes ou des macrophages, dans ce modèle tissulaire in vitro, est dépendante de ROCK et des protéases, signature de l'utilisation des deux modes migratoires. Puis en incubant ces sphéroïdes au sein de MEC, j'ai démontré que la présence de macrophages infiltrés dans les sphéroïdes est nécessaire pour déclencher le pouvoir invasif des cellules tumorales qui émigrent des sphéroïdes en suivant les macrophages et infiltrent la MEC environnante. Les macrophages Hck-/- présentant un défaut de migration mésenchymale, sont significativement moins efficaces dans la promotion de l'invasion des cellules tumorales. Ces résultats indiquent que l'activité de migration et de remodelage de la matrice exercée par les macrophages est prépondérante dans l'invasion tumorale in vitro. Ces résultats ont permis d'établir le mode migratoire des macrophages infiltrant un modèle tissulaire in-vitro et de démontrer le mécanisme d'action des macrophages dans l'invasion tumorale. Ainsi, mes travaux de thèse ont permis de progresser dans la caractérisation des mécanismes moléculaires et cellulaires de la migration 3D des macrophages humains. En effet, j'ai pu 1) identifier une protéine nécessaire à la migration mésenchymale des macrophages, 2) mettre en évidence l'utilisation par les macrophages des modes migratoires amiboïde et mésenchymal lors de leur infiltration dans un modèle de tumeur en trois-dimensions, les sphéroïdes tumoraux et 3) montrer que le remodelage de la matrice par les macrophages, lors de leur migration, joue un rôle prépondérant dans l'invasion tumoraleTissue infiltration of macrophages is an aggravating factor in many diseases such as chronic inflammation and cancer. Macrophages that infiltrate tumors are called tumor-associated macrophages (TAMs). They promote tumor growth, angiogenesis, invasion and metastasis. Thus, inhibition of macrophage infiltration has become a therapeutic goal. Recently, the team demonstrated that macrophages use the amoeboid (depending on ROCK) or the mesenchymal (depending on proteases) migratory mode according to the extracellular matrix (ECM) architecture in three dimensions (3D). In addition, the study of the mesenchymal migration mode showed that it is dependent on Hck (a phagocyte-specific tyrosine kinase) and its ability to reorganize podosomes (ECM-degrading actin-rich structures) into rosettes. My thesis project was organized around two axes 1) the identification of substrates of Hck and the characterization of their role in the organization of podosomes and 3D migration of macrophages, and 2) the study of the 3D migration mechanisms of primary human monocytes/ macrophages within an in vitro tumor model: tumor cell spheroids. By a proteomic approach, I have identified potential partners and substrates of Hck, including the protein Filamin A (FLNa), a protein interacting with the actin cytoskeleton and integrins. Using different tools (recombinant proteins, antibodies, shRNA. . . ) I showed that: 1) Hck phosphorylates FLNa in vitro, 2) FLNa is localized to podosomes and is necessary for their organization as rosettes under the control of Hck, 3) the podosomes of FLNa-deficient cells have a shorter life span, and 4) the expression of FLNa is required for mesenchymal migration, but not for amoeboid migration of macrophages in a 3D ECM. Thus, FLNa could be a substrate of Hck necessary for the formation and stabilization of podosomes and their organization as rosettes, and is required for the mesenchymal migration of macrophages. In parallel, I developed a model of tumor cell spheroids, which allowed me to show that the infiltration of monocytes or macrophages in this in vitro tissue model of tumor is dependent on ROCK and proteases, signature of the use of the two migration modes. Then, when spheroids were embedded into ECM, I demonstrated that the presence of macrophages infiltrated into the spheroids is necessary to trigger the invasiveness of tumor cells. Indeed, macrophages infiltrate first the surrounding ECM and tumor cells follow macrophages in the matrix outside of the spheroid. Hck-/- macrophages, that are defective in mesenchymal migration, are significantly less effective in promoting the invasion of tumor cells. These results indicate that the activity of migration and matrix remodeling exerted by macrophages is prominent in tumor invasion. These results have established the migratory mode of macrophages infiltrating an in vitro tumor model and a mechanism required for tumor invasiveness promoted by macrophages. Thus during my thesis, I characterized the molecular and cellular mechanisms of 3D migration of human macrophages. Indeed, I have been able to: 1) identify a protein necessary for the mesenchymal migration of macrophages, 2) highlight the use by macrophages of the amoeboid and mesenchymal migration modes during their infiltration into an in vitro tumor model in 3D and 3) show that the matrix remodeling activity of macrophages during their migration plays a critical role in tumor cell invasion
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Wendel, Caroline. "In Vitro Study of Recruitment Ability of Macrophages and Trophoblasts in Early Human Pregnancy." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56818.
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The tolerance towards the semi-allogenic foetus is obtained through both systemic and local changes in the maternal immune response. Locally, in the decidua, the cell composition differs from that found in the blood; natural killer (NK) cells and macrophages being the major cell types. Decidual macrophages (dMØ), which are alternatively activated, and trophoblasts, placental cells of foetal origin, are believed to participate in the foetal tolerance at the foetal-maternal interface. To test the recruitment ability of macrophages and trophoblasts, and to test if these cells are responsible for the special cell composition in the decidua, a migration assay was established. In this migration assay peripheral blood mononuclear cells (PBMC) were allowed to migrate through Matrigel-coated transwell inserts into lower wells containing a recruiting stimulus. After testing several conditions, a protocol was established for further use. The results showed that in vitro alternatively activated macrophages, which display many of the surface markers as dMØ, hold a recruiting ability and recruit monocytes. Further there was an indication that trophoblasts also hold a recruiting ability. Neither cell types were shown to recruit NK cells. In conclusion, this study presents a suitable protocol for assessing chemotactic factors and different cell type’s ability to recruit cells from blood. Although the experiments need to be repeated and extended and the recruitment ability of dMØ needs to be evaluated in detail before a final conclusion can be drawn, the preliminary data indicated that macrophages and trophoblasts can recruit monocytes.
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Lo, Wing-sze, and 盧詠詩. "The role of macrophage migration inhibitory factor in the pathogenesisof acute graft-versus-host disease following allogeneic bone marrowtransplantation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31226413.
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Lacey, Derek. "NFκB independent pathway activation of rheumatoid arthritis FLS by macrophage migration inhibitory factor (MIF)." Monash University, Faculty of Medicine, 2003. http://arrow.monash.edu.au/hdl/1959.1/9457.
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Poincloux, Renaud. "Etude du rôle du proto-oncogène Hck, tyrosine kinase de la famille Src, au cours de la migration trans-tissulaire des phagocytes." Toulouse 3, 2006. http://www.theses.fr/2006TOU30300.
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Powell, Nicole Damico. "Immunomodulation of experimental autoimmune encephalomyelitis targeting the autoreactive T cell and the cytokine macrophage migration inhibitory factor /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141052089.
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Jing, Chenzhi. "Characterisation of the effect and functional significance of Fcγ receptor crosslinking on metabolic processes in macrophages." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/280316.
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The metabolic state of an immune cell directly influences its ability to function and differentiate, ultimately affecting immunity, inflammation and tolerance. Different immune cell subsets have differing metabolic requirements. Macrophages, as the frontline, tissue-resident cells of the innate immune system, undergo profound metabolic reprogramming in response to environmental stimuli. To date, there has been little consideration how macrophage metabolism might be affected by humoral immunity. IgG antibodies are the soluble effector molecules of the adaptive humoral immune system. Fcγ receptors (FcγRs) mediate the cellular functions of IgG antibodies and are expressed on most immune cells including macrophages. FcγR cross-linking induced by IgG immune complexes (ICs) is important for defence against some infections but can also play a pathogenic role in autoimmunity. Here, I studied the metabolic reprogramming induced in macrophages by IgG IC ligation of FcγRs. I first investigated how FcγRs cross-linking might impact glucose metabolism. We show that macrophages undergo a switch to glycolysis in response to IgG IC stimulation. FcγR-associated glycolysis was dependent on the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF)1α. Moreover, this glycolytic switch was required to generate a number of pro-inflammatory mediators and cytokines. Inhibition of glycolysis, or genetic depletion of HIF1α in macrophages resulted in the attenuation of IL1β and other inflammatory mediators produced in response to IgG IC in vitro. To determine the relevance of these observations to responses to IgG IC in vivo and, in particular, to IC-associated tissue inflammation in autoimmune diseases such as system lupus erythematosus (SLE), I developed three models to interrogate tissue macrophages. Following administration of IC to peritoneal macrophages, I observed IL1β-associated neutrophil recruitment that was abrogated by inhibiting glycolysis, or in the presence of HIF-1a deficiency. Similarly, following administration of intravenous IC, or nephrotoxic serum, kidney macrophage activation was abrogated by glycolysis inhibition or by myeloid HIF-1a deficiency. Together my data reveal the cellular molecular mechanisms required for FcγR-mediated metabolic reprogramming in macrophages and define a novel therapeutic strategy in autoantibody-induced inflammation. In the final part of the thesis I identified additional metabolic pathways that were altered by FcγR ligation, including cholesterol biosynthesis and fatty acid biosynthesis. This has important implications for protective immune responses and autoimmune susceptibility, since a number of intermediates in these pathways can directly regulate and contribute to immune responses. In summary, I have demonstrated the metabolic alterations triggered by FcγR ligation, reveal the cellular molecular mechanisms required for FcγR-mediated cellular respiration reprogramming in macrophages and define a potential therapeutic target in autoimmunity.
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Rakhila, Halima. "Mise en évidence de dysfonctions liées au développement de l'endométriose péritonéale : contributions angio-inflammatoires des cytokines et prostaglandines." Doctoral thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/26860.
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L'endométriose est une maladie gynécologique, touchant les femmes en âge de procréer. Cette pathologie est caractérisée par la présence de tissu endométrial ectopique, c'est-à-dire en dehors de la cavité utérine. Des dysfonctions du système immunitaire sont de plus en plus souvent suspectées comme étant un des éléments responsables de la pathogenèse de cette maladie. L’objectif général de ce projet a donc été d’étudier les mécanismes cellulaires de molécules pro-inflammatoires aux propriétés variées et à l'expression anormalement élevée dans cette pathologie, que sont MIF et les prostaglandines PGE2 et PGF2α, dans les anomalies inflammatoires et invasives en cause dans cette pathologie. La première partie de nos travaux a porté sur l’étude d’un modèle murin de l’endométriose déficient du gène MIF. Le nombre et le volume des lésions collectées à partir des souris déficientes pour le gène MIF sont significativement inférieurs à ceux mesurés dans des souris sauvages utilisées comme contrôle. L’analyse par PCR des cellules isolées des lésions de souris déficientes du gène MIF a révélé une expression réprimée des protéines d’adhésion, d’inflammation et d’angiogenèse. Ces données démontrent pour la première fois que le MIF agit directement sur la croissance et la progression de lésions d’endométriose in vivo. Une partie de nos travaux a porté sur les molécules nécessaires au métabolisme de PGE2 et PGF2α dans l'endomètre eutopique des femmes normales et l'endomètre eutopique et ectopique des femmes atteintes d'endométriose. Selon nos données, l'expression de certains de ces facteurs est perturbée durant cette maladie, ce qui peut avoir des effets délétères sur la physiologie de la procréation. La stimulation des cellules ectopiques par PGF2α entraîne une libération accrue de VEGF et CXCL-8, ceci via l'induction de COX-2 et des deux variants d’épissage du récepteur FP. De plus, la PKC joue un rôle dans ce phénomène, dépendamment et indépendamment de la PLC. Par son effet inducteur sur la libération de VEGF et CXCL-8, PGF2α pourrait favoriser l'aspect inflammatoire et le développement ectopique des lésions d'endométriose, notamment par des phénomènes d’angiogenèse et de prolifération cellulaire accrus. L'effet de PGF2α sur la libération de VEGF et CXCL-8 par les cellules endométriales ectopiques pourrait également expliquer les quantités élevées de ces cytokines dans le liquide péritonéal des femmes atteintes d'endométriose, un phénomène suspecté dans l'infertilité et les douleurs associées à cette maladie. Nos derniers résultats obtenus à partir du liquide péritonéal montrent un profil cytokinique en faveur de l’angiogenèse et la prolifération des lésions d’endométriose, avec une forte augmentation des facteurs suivants : EGF, FGF-2, IL-1α, MIP-1β, TGFα, PDGF-AA, PDGF-BB, MCP-3, sCD40L, Gro Pan, IL-17α, MDC et Rantes, confortant nos observations préalables redéfinissant la maladie comme étant d’origine angio-inflammatoire. L'endométriose et ses symptômes sont des phénomènes complexes ayant probablement plus qu'une seule origine. Parmi les nombreux facteurs à l'expression altérée dans l'endométriose, notre étude montre que MIF, PGE2 et PGF2α, ainsi qu’une pléthore de facteurs pro-angiogéniques pourraient être de ceux jouant un rôle dans l'infertilité et les douleurs reliées à cette maladie.Endometriosis is a menstrual disorders, is mainly diagnosed in the peritoneal cavity by the presence of lesions, which are thought to originate from the endometrium. Little is known about the causes of endometriosis and no targeted treatment is available. Our studies were the first to show functional defects involving the immune system in the endometrium, i.e. before this tissue migrates and grows into abnormal locations. Our current main hypothesis is that endometriosis development requires a combination of immune dysfunction involving factors, such as MIF, PGE2 and PGF2α. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngenic wild type (WT) mice and vice versa, we first revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant downregulation of the expression of major inflammatory, cell adhesion, survival and angiogenic factors relevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis. We then revealed for the first time multiple defects in PG biosynthesis and receptivity pathways, which differ between eutopic intrauterine and ectopic endometrial tissues and may, owing to the wide spectrum of PG properties, contribute to the initial steps of endometrial tissue growth and development and have an important role to play in the pathogenesis and symptoms of this disease. Afterward, we focussed on PGF2α which markedly up-regulated PGE2, CXCL-8 and VEGF secretion in endometriotic cells, through COX-2 activation. Such an effect was abolished by AL8810, a specific FP antagonist, and significantly down-regulated after specific inhibition of FP different variants signalling pathways. PGF2α enhanced angiogenesis through endothelial tubal formation and proliferation processes. These results show for the first time that PGF2α exerts an indirect angiogenic effects by interacting with ectopic stromal cells and induces the secretion of major angiogenic factors via FP signalling pathways. This study provides evidence for a new mechanism underlying endometriosis development and pathophysiology. As our last data showed distinct patterns of peritoneal fluid cytokine concentrations in endometriotic women most notably a marked increase in EGF, FGF-2, IL-1α, MIP-1β, TGFα, PDGF-AA, PDGF-BB, MCP-3, sCD40L, Gro Pan, IL-17α, MDC and Rantes. These changes may exacerbate the local peritoneal angiogenic and proliferative reaction observed in women with endometriosis, and contributes to its pathophysiology. Inflammation is a major hallmark of endometriosis and angiogenesis is crucial to ectopic endometrial tissue growth. Once viewed as archetypical mediators of inflammation and pain, prostaglandins and angiogenic cytokines should be now regarded major promoters of endometriotic lesions growth.
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Allaire, Marc-André. "Étude de l'implication de la prostaglandine E[indice inférieur]2 dans la signalisation cellulaire menant à la chimiotaxie des monocytes vers les ligands CCL19/CCL21 et l'impact de la maturation des monocytes en macrophages sur leur récepteur CCR7." Mémoire, Université de Sherbrooke, 2013. http://hdl.handle.net/11143/6567.
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Le Récepteur de chimiokine CCR7 joue un rôle important dans la migration des cellules immunitaires, permettant ainsi l'initiation de la réponse immunitaire. Des études ont démontré qu'une déficience dans l'expression de ce récepteur ou de ces ligand CCL19 et CCL21 a un impact considérable sur la mise en place de la réaction immunitaire suite a un stimulus. D'autre part la prostaglandine de série E 2 a été identifié comme un agent régulateur important sur l'expression et la fonctionnalité du récepteur CCR7 dans l'établissement de la réponse immunitaire, principalement au niveau des cellules dendritiques. L'élévation du niveau de prostaglandine E 2 , lors de certaine infection, induit une augmentation importante de la migration des cellules immunitaires, lors de l'activation du récepteur CCR7. Ces cellules vont alors migrer vers ses ligands qui sont produit principalement au niveau des ganglions lymphatique, permettant ainsi la présentation antigénique aux cellules du système immunitaire adaptatif. Récemment, des travaux ont permis de mettre en évidence l'expression du récepteur CCR7 chez les monocyte et du rôle important de la PGE 2 dans l'expression et la fonctionnalité du récepteur chez ces cellules. Les travaux réalisés dans le cadre de cette maîtrise avaient pour but, dans un premier temps, de déterminer les mécanismes moléculaires permettant la migration cellulaire des monocytes suite à l'activation du récepteur CCR7 par la présence de son ligand CCL19. Nous avons également vérifié l'implication de la PGE 2 dans ce processus. Partant des mécanismes connus chez les cellules dendritiques et des cellules T, nous avons établi que la participation des MAPK p38, ERK et JNK sont importantes dans ce processus. La présence de PGE2 permet une phosphorylation plus rapide de ses MAPK. Nous avons ensuite vérifié la participation de la voie RhoA/ROCK, importante dans le réarrangement du cytosquelette d'actine. L'activation du récepteur CCR7 par son ligand CCL 19 permet une activation de RhoA. Cette activation survient plus rapidement lorsque les cellules sont en présence de PGE 2. Lorsque ces voies métaboliques sont bloquées par des inhibiteurs pharmacologiques, la migration des monocytes est alors inhibée, démontrant l'importance de ses voies pour la migration des monocytes vers les ligands CCL191 Dans un second temps, nous avons étudié l'impact de la maturation des monocytes en macrophage sur le récepteur CCR7. Jusqu'à maintenant, il est connu que la PGE2 permet une augmentation de l'expression de CCR7 chez les monocytes et augmente la réponse chimiotactique des cellules vers les ligands de CCR7. De plus on sait que lors de la maturation des monocytes en cellules dendritique mature, une forte augmentation de l'expression du récepteur CCR7 est observé et que la présence de PGE 2 est essentielle pour assurer la fonctionnalité du récepteur. Toutefois, l'impact de la maturation des monocytes en macrophage sur le récepteur CCR7 est encore inconnu. Nous avons alors démontré que lors de la maturation des monocytes en macrophages, il y a une importante perte de l'expression du récepteur CCR7 et que la présence inflammatoire de la PGE 2 ne permet pas une augmentation de l'expression du récepteur et de la migration des cellules chers les ligands de CCR7. La migration des macrophages vers les ganglions lymphatique ne serait alors pas attribuée à la chimiotaxie de CCR7 vers ses ligands. Ces travaux ont permis de mettre en lumière les principaux acteurs moléculaires impliqué dans la migration des monocytes suite à l'activation du récepteur CCR7 et que la PGE2 permettrait aux monocytes de migrer préférentiellement vers ses ligands au lieu de transmigrer vers les tissus où ils se différencieraient en macrophage. Suite à la différenciation des monocytes en macrophages, nous avons également pu démontrer qu'ils n'ont plus la capacité d'exprimer le récepteur CCR7 et amorcer leur migration vers les ligands CCL19 et CCL21 exerçant ainsi leur fonction en tant que cellules résidente des tissus.[ symboles non conformes]
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Villeneuve, Jérôme. "Influence de l'immunité et des facteurs angiogéniques sur la croissance des glioblastomes." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27183/27183.pdf.
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Carli, Cédric. "Les dysfonctions immuno-inflammatoires dans l'infertilité associée à l'endométriose : implications du facteur de la migration des macrophages (MIF) et de la prostaglandine E2 (PGE2)." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26052/26052.pdf.
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Loyher, Pierre-Louis. "Rôle du récepteur de chimiokines CCR2 dans la dynamique des lymphocytes T régulateurs et monocytes/macrophages en réponse aux thérapies antitumorales." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066010/document.
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Une forte production de la chimiokine CCL2 par les cellules malignes et les cellules stromales a été démontrée dans la plupart des cancers humains. Ainsi, l’axe chimiokinique CCR2/CCL2 est un important marqueur du développement des cancers ; ce même axe est associé à la récurrence de tumeurs après thérapie anticancéreuses. Les macrophages associés aux tumeurs (TAM) et les lymphocytes T régulateurs (Treg) ont des capacités immunosuppressives robustes et contribue à la croissance tumorale. Durant cette thèse, je me suis intéressé à la fonction de l’expression du récepteur de chimiokine CCR2 par ces cellules dans le contexte de thérapies anticancéreuses. Nous avons montré que le récepteur de chimiokines CCR2 contrôle la migration des Treg en contexte tumoral, chez l’homme et la souris, et que son expression par les Treg peut servir de biomarqueur de la réponse à la chimiothérapie. Notre étude indique une nouvelle fonction de CCR2 et définie un nouveau sous-type de Treg impliqué dans la régulation de l’immunité antitumorale. En parallèle, nous avons pu mettre en évidence que les métastases pulmonaire sont composées à la fois de macrophages résident du tissu et de macrophages recrutés via l’axe CCR2. La présence de macrophages résidents au sein des tumeurs pourrait contribuer à l’hétérogénéité des microenvironnements de diffèrent type de tumeurs. Le récepteur CCR2 est important pour le la phase de rechute après chimiothérapie, indiquant un rôle limité des macrophages résidents dans ce phénomène. De plus, nous avons montré que le VEGF joue un rôle direct dans la survie des TAM. Ainsi, la combinaison de la chimiothérapie avec un anticorps anti-VEGF cible simultanément les TAM résidents et recrutés et permet d’augmenter l’efficacité de la chimiothérapieMalignant and stromal cells are strong producer of the chemokine CCL2 in most human cancers. The chemokine axis CCR2/CCL2 is thus a key marker of cancer development, but is also associated with relapse following therapy. Tumour associated macrophages (TAM) and regulatory T cells (Treg) display robust immunosuppressive capacities and contribute to tumour growth. My thesis work focused on the function of the expression of the chemokine receptor CCR2 by these cell types in the context of anticancer therapies. We have shown that CCR2 controls the migration of Treg in tumoral context, in both human and mice, and that the expression of this receptor by Treg could serve as a biomarker of the response to chemotherapy. Our study indicate a novel function of CCR2, defining at the same time a new Treg subset implicated in the regulation of antitumor immunity.We have also demonstrated that pulmonary metastases are composed of both tissue resident and recruited macrophages. The presence of resident macrophages within tumours could contribute to the heterogeneity of the microenvironment of different tumour types. CCR2 is largely implicated in the relapse phase following chemotherapy, indicating a limited role for resident macrophages in this phenomenon. Meanwhile, we have demonstrated that VEGF plays a direct role in TAM survival. The combination of chemotherapy with an anti-VEGF antibody targets both resident and recruited TAM, thereby enhancing the efficacy of chemotherapy. Finally, we have shown that the CCR2/CCL2 axis is implicated in the response to radiotherapy by enhancing the recruitment of both Treg and TAM. This work provides evidences for a central role of the CCR2/CCL2 axis in mediating Treg and TAM co-localization in response to anticancer therapy, this axis could also contribute to establishment of immunosuppressive networks in tumours. Our results provide a better understanding of the immune mechanism implicated in resistance to anticancer therapies
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Baeza, Garcia Alvaro. "Rôle de MIF (Macrophage Migration Inhibitory Factor) dans l'immunité innée et la réponse anti-schistosome chez Biomphalaria glabrata." Phd thesis, Université du Droit et de la Santé - Lille II, 2010. http://tel.archives-ouvertes.fr/tel-00665113.
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Schistosoma mansoni est un parasite helminthe responsable de la schistosomiase intestinale, qui affecte 200 millions de personnes dans les zones tropicales et subtropicales, et l'on estime que 600 millions de personnes sont exposées au risque de cette infection. Le cycle de vie du parasite est complexe et il requière, un hôte définitif, l'homme et un hôte intermédiaire, un mollusque d'eau douce appelé Biomphalaria glabrata. C'est chez le mollusque où le parasite se multiplie de forme massive de là l'importance du mollusque dans la transmission du parasite à l'homme. Lors de l'infection le mollusque met en place une réponse cellulaire et humorale très marquées pouvant dans certains cas tuer le parasite. Malgré l'importance du mollusque, les mécanismes moléculaires qui gouvernent ces réponses sont largement inconnus et donc l'étude de l'immunité du mollusque est une priorité en recherche médicale. Nous avons identifié deux orthologues de la cytokine de mammifère MIF (Macrophage Migration Inhibitory Factor ) BgMIF1 et BgMIF2. En utilisant des approches biochimiques et moléculaires en combinaison avec la technique de RNAi in vitro et in vivo nous avons démontré le rôle de BgMIF 1 et BgMIF2 comme régulateurs centrales de l'immunité innée du mollusque. En particulaire BgMIF1 régule l'activation des hémocytes et la réponse d'encapsulation lors de l'infection. D'un autre côté BgMIF2 régule dans la réponse antibactérienne. Nos résultats montrent que chez B. glabrata il y une régulation fine de la réponse immune innée et une capacité pour répondre de façon différente lors d'un challenge immunitaire. De plus une régulation par une cytokine de type vertébré dans un invertébré n'avait jusqu'à présent jamais été décrite. Nos travaux établissent les bases pour mieux comprendre les relations hôte-parasite dans une maladie comme la schistosomiase, et aussi constituent une avancée importante du point de vue de l'évolution de l'immunité innée en général.l
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Reis, Maria Danielma dos Santos. "Papel funcional do hormônio do crescimento sobre macrófagos peritoneais de camundongos." Universidade Federal de Alagoas, 2011. http://repositorio.ufal.br/handle/riufal/946.
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Studies have shown that growth hormone (GH) is a polypeptide with immunomodulatory properties. Herein, studies were performed to determine in vivo and in vitro effects of GH on macrophage by using cultures of resident peritoneal macrophages from swiss mice. The microscopical analyses revealed alterations in the macrophage morphology after GH treatment with 20 and 200 ng/mL for 12 and 24 hours. It was also observed that GH-treated macrophages have an increase in fibronectin and laminin deposition evaluated by indiret immunocytochemistry. By using flow cytometry, it was shown that GH-treatment (200 ng/mL) for 6 and 24 hours altered the Mac-1 and VLA-6 integrins expression on macrophage surface. Moreover, the same GH concentration, during 6 hours of treatment, was able to decreased macrophage adhesion to laminin. In the in vitro migration assays, the GHtreated cells (200 ng/mL) showed opposite effects depending on the treatment time, after 6 hours, there was a increase in migrating cells whereas after 12 hours was a decrease in cell migration. The in vitro GH treatment did not influence the phagocytic activity of macrophages but when the GH treatment was perfomed in vivo, for 7 consecutive days, the peritoneal macrophages from GH-treated mice (20 and 200 μg/kg) showed a higher porcentage of phagocytosis and also a higher phagocytic capacity than cells from control animals. Taken together, these results reinforce the literature data which show that GH can act as an macrophage activating-factor in the immune response.Fundação de Amparo a Pesquisa do Estado de Alagoas
Estudos mostram que o hormônio do crescimento (GH) é um polipeptídio com propriedades imunomoduladoras. Assim, o objetivo desse estudo foi avaliar os efeitos in vivo e in vitro do GH sobre macrófagos, utilizando culturas de macrófagos peritoneais residentes obtidos de camundongos swiss. Inicialmente, através da análise microscópica foram observadas alterações na morfologia dos macrófagos em cultura, tratados com GH, nas concentrações de 20 e 200 ng/mL, pelos períodos de 12 e 24 horas, quando comparado às células não-tratadas. A presença de ligantes de moléculas da matriz extracelular em macrófagos foi analisada por imunocitoquímica, em que se evidenciou um aumento na deposição de fibronectina e laminina quando as células foram tratadas com GH nas concentrações de 20 e 200 ng/mL, nos tempos de 6, 12 e 24 horas. Por citofluorimetria, observou-se que o tratamento com GH (200 ng/mL), por 6 e 24 horas alterou a expressão das integrinas Mac-1 e VLA-6 na superfície dos macrófagos. Além disso, o tratamento com GH, nesta mesma concentração, pelo período de 6 horas, foi capaz de diminuir a adesão de macrófagos à laminina. No ensaio de migração in vitro, o tratamento com GH (200 ng/mL), apresentou efeitos opostos nos diferentes tempos de tratamento, aumentando o número de células migrantes após 6 horas e diminuindo o número de macrófagos migrantes após 12 horas de tratamento. Demonstrou-se ainda, que o tratamento in vitro com GH, em ambas as concentrações, não modulou a atividade fagocítica dos macrófagos, contudo macrófagos peritoneais obtidos de animais tratados com GH nas doses de 20 e 200 μg/kg, por um período de 7 dias, apresentaram uma maior porcentagem de fagocitose e uma maior capacidade fagocítica quando comparados aos macrófagos de animais do grupo controle. De uma forma geral, os resultados apresentados reforçam os dados já constantes na literatura de que o GH pode agir na resposta imune como um ativador de macrófagos.
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Herrmann, Lavoie Catherine. "Étude des mécanismes de régulation des récepteurs de l'interleukine-1 dans l'endomètre humain par la hCG et du facteur inhibiteur de la migration des macrophages dans l'endométriose par l'interleukine-1." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24309/24309.pdf.
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Khanna, Ankita, Pouya Lotfi, Anita J. Chavan, Nieves M. Montaño, Parvin Bolourani, Gerald Weeks, Zhouxin Shen, et al. "The small GTPases Ras and Rap1 bind to and control TORC2 activity." NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/614747.
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Target of Rapamycin Complex 2 (TORC2) has conserved roles in regulating cytoskeleton dynamics and cell migration and has been linked to cancer metastasis. However, little is known about the mechanisms regulating TORC2 activity and function in any system. In Dictyostelium, TORC2 functions at the front of migrating cells downstream of the Ras protein RasC, controlling F-actin dynamics and cAMP production. Here, we report the identification of the small GTPase Rap1 as a conserved binding partner of the TORC2 component RIP3/SIN1, and that Rap1 positively regulates the RasC-mediated activation of TORC2 in Dictyostelium. Moreover, we show that active RasC binds to the catalytic domain of TOR, suggesting a mechanism of TORC2 activation that is similar to Rheb activation of TOR complex 1. Dual Ras/Rap1 regulation of TORC2 may allow for integration of Ras and Rap1 signaling pathways in directed cell migration.
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Batista, Érika Cássia Barroso. "Migração de células precursoras miogênicas sob a influência de sobrenadantes de macrófagos irradiados com laser de baixa potência." Universidade Nove de Julho, 2015. http://bibliotecatede.uninove.br/handle/tede/1802.
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The activation, proliferation and migration of myogenic precursor cells are essential for muscle regeneration after injury, orchestrated by cells and local components, mainly inflammatory cells, especially macrophages. These are identified as a target for the treatment of muscle injuries. Laser therapy has shown good results in treatment of injuries and the ability to accelerate the migration of various cell types, but there are no reports on their effect on macrophage products influencing the migration of myogenic precursor cells. The aim of the study was to evaluate the effect of low level laser (LLL) on migration of myoblasts cultured with macrophage culture supernatants of different phenotypes. Therefore, C2C12 cells were cultured with supernatants from cultures of macrophages (J774) treated with LPS and IFN-γ (for the activation phenotype M1), IL-4 (M2a phenotype) and IL-10 and dexamethasone (M2c phenotype) and LLL irradiated at wavelengths of 660nm and 780nm (70mW; 17,5J / cm2; 14.3 s; 0,8J). Supernatants from macrophage cultures were harvested 24h after irradiation and transferred to myoblast cultures. Migration was assessed using the scratch assay and the results statistically analyzed. Myoblasts cultured with phenotype macrophage supernatants M2c and irradiated with LBP (660nm) showed higher migration capability that cultured with supernatants of M2C phenotype of macrophages after 12 hours of cultivation. There was no difference between the other groups. The LLL was able to modulate the migration of myoblasts C2C12 when M2c supernatants of macrophage phenotype
A ativação, proliferação e migração das células precursoras miogênicas são essenciais na regeneração muscular após lesões, orquestrados pelas células e componentes locais, principalmente pelas células inflamatórias, em especial os macrófagos. Estes são apontadas como alvo para o tratamento das lesões musculares. A laserterapia tem demonstrado bons resultados no tratamento destas lesões e na capacidade de acelerar a migração de vários tipos celulares, mas não existem relatos sobre seu efeito nos produtos de macrófagos que influenciam a migração de células precursoras miogênicas. O objetivo do estudo foi avaliar o efeito do laser de baixa potência (LBP) sobre a migração de mioblastos cultivadas com sobrenadantes de culturas de macrófagos de diferentes fenótipos. Para tanto, as células C2C12 foram cultivadas com sobrenadantes de culturas de macrófagos (J774) tratadas com LPS e IFN- γ (ativação para o fenótipo M1), IL-4 (fenótipo M2a) e IL-10 e dexametasona (fenótipo M2c) e irradiadas com LBP nos comprimentos de onda de 660nm e 780nm (70mW; 17,5J/cm2; 14,3 s; 0,8J). Os sobrenadantes das culturas de macrófagos foram colhidos 24h após as irradiações e transferidos para culturas de mioblastos. A migração foi avaliada por meio do ensaio de ferida e os resultados submetidos à análise estatística. Após 12h de cultivo, os mioblastos cultivados com sobrenadantes de macrófagos de fenótipo M2c e irradiados com LBP (660nm) mostraram maior capacidade de migração que os cultivados com sobrenadantes de macrófagos de fenótipo M2c não irradiados. Não houve diferença entre os demais grupos. O LBP foi capaz de modular a migração de mioblastos C2C12 quando cultivados com sobrenadantes de macrófagos de fenótipo M2c.
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Yates, Matthew. "Studies on macrophage migration in pathological contexts." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/53465/.
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Macrophages play key roles following nerve injury releasing cytokines and chemokines thought to be involved in the development and maintenance of neuropathic pain. ATP is a transporter of chemical energy, but can also act as an extracellular signalling molecule that signals through purinergic receptors. ATP, probably released from damaged neurons, can promote the migration of macrophages and microglia to the site of injury, and can be responsible for the onset of neuropathic pain. Purinergic signalling via ATP and other nucleotides is now well established and increasing evidence suggests that ATP could play important roles in pathophysiology. The neuroprotective neurotrophin brain derived neurotrophic factor (BDNF) inhibited ATP-induced invasion of macrophages though an extracellular matrix. The well-characterised Sigma-1 Receptor chaperone, previously implicated in BDNF function, was shown to be an important overall regulator of macrophage invasion, and to be potentially implicated in BDNF suppression of ATP-induced invasion. BDNF may thus have a neuroprotective role to inhibit further macrophage recruitment to the site of injury. Matrix metalloproteinases (MMPs) are capable of remodelling the extracellular matrix and the activation of inflammatory mediators. Exploration of MMP responses to extracellular ATP stimulation in a macrophage cell line revealed that MMPs -8, -12, and-13 as well as TIMP-2 steady state mRNA levels were significantly up-regulated ATP, ATP can alter matrix remodelling. Macrophage recruitment is a significant player in atherosclerosis and may be modulated by Apolipoprotein E genotype. N3-polyunsaturated fatty acids (obtained from dietary fish oils) have been implicated in cardiovascular protection. Using a high fat diet model the effects of dietary fish oil supplementation and Apolipoprotein E subtype were explored in ex vivo primary macrophages. Unexpectedly, a fish oil supplemented diet led increased macrophage migration speed and reduced TIMP-2 mRNA levels, suggesting that fish oil supplements play complex roles in atherosclerotic-related scenarios.
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Hansson, Annika. "The effects of plasminogen deficiency on the healing of tympanic membrane perforations." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1100.
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Dessein-Pouchelle, Anne-Frédérique. "Induction par le couple MIF-CXCR4 d'un phénotype invasif et métastatique au sein de cellules tumorales coliques humaines chimiorésistantes." Lille 2, 2009. http://www.theses.fr/2009LIL2S037.
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Contexte : Malgré le développement de thérapies combinées utilisant des agents anticancéreux cytotoxiques et/ou des thérapies ciblant les voies de signalisation oncogénique, la persistance de cellules tumorales agressives reste un obstacle majeur au traitement des cancers. Objectif : Le but de ce travail était d'analyser les mécanismes moléculaires de la survie et de l'agressivité métastatique de cellules cancéreuses coliques chimiorésistantes. Méthode : La recherche d’éléments impliqués dans l’agressivité métastatique et la résistance aux drogues a été réalisée en combinant les approches de transcriptome, RT-PCR quantitative, Western Blot, ELISA et cytométrie en flux. L’étude du potentiel métastatique a été effectuée en utilisant les techniques d’invasion in vitro sur collagène de type I et de xénogreffes sous-cutanées sur modèles murins. L’étude des mécanismes responsables a fait appel à des inhibiteurs pharmacologiques, des anticorps bloquants et à la technique d’invalidation génique par ARN interférence. Résultats : Nous avons caractérisé des cellules HT-29 chimiorésistantes spontanément invasives dans une matrice de collagène de type I et spontanément métastatiques in vivo dans des modèles de xénogreffes souscutanées, versus des cellules non invasives et non métastatiques. Une approche transcriptomique comparative sur puces pangénomiques a permis de mettre en évidence la surexpression très importante d’un récepteur de chimiokine, CXCR4, dans les cellules invasives comparativement aux cellules non invasives. La cytokine MIF a été identifiée comme le ligand autocrine de CXCR4 responsable de l’invasion cellulaire. L’invalidation de CXCR4 et le ciblage pharmacologique de l’axe MIF/CXCR4 abolissent ce phénotype agressif. L’induction de CXCR4 est associée à la surexpression de HIF-2! et ASCL2, deux facteurs de transcription impliqués dans le contrôle de l’expression de CXCR4 et la maintenance des cellules souches intestinales. Une étude pilote effectuée sur une série de métastases hépatiques issues de patients atteints de cancer colorectal a révélé une augmentation significative et importante des transcrits de CXCR4 chez les patients ayant suivi une chimiothérapie néo-adjuvante par le protocole FOLFOX. Conclusion : Le ciblage de l’axe CXCR4/MIF en association thérapeutique pour le traitement du cancer colorectal pourrait contrecarrer l’émergence d’un comportement invasif et métastatique au sein de populations clones de cellules tumorales coliques chimiorésistantes.
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Larson, Douglas, and Katherine Horak. "Macrophage migration inhibitory factor: controller of systemic inflammation." BioMed Central, 2006. http://hdl.handle.net/10150/610128.
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Macrophage migration inhibitory factor (MIF) is a cytokine that is secreted by the anterior pituitary and immune cells in response to surgical stress, injury, and sepsis. This cytokine appears to be a critical regulator of the inflammatory pathways, leading to systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome. This report provides an integrated scheme describing the manner by which MIF controls the neurohormonal response and the adaptive immune system, namely the T-helper (Th)1 and Th2 lymphocytes, which results in the release of pro-inflammatory cytokines and the anti-inflammatory cytokine interleukin-10. The development of systemic inflammatory response syndrome and subsequent development of multiple organ dysfunction syndrome appear to be related to MIF levels and the balance of Th1 and Th2 function.
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Montero, Rosa Maria. "Chemokines and macrophage migration inhibitory factor in diabetic nephropathy." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29851.
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Introduction: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the Western world. Aim: To determine whether macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) or CC chemokine ligand 18 (CCL18) have a causative role in the development of renal inflammation and fibrosis in DN and are useful biomarkers of disease progression. Methods: Urine and plasma samples were collected from 115 DM and 116 Non-DM at baseline, previously analysed for MCP-1 and CCL18 ELISA by Dr Qureshi. I measured MIF in these samples and collected 107 DM and 114 Non-DM data points (GFR, ACR/UPCR and clinical parameters) at >18 months and >3 years. MIF, MCP-1 and CCL18 urine, plasma and serum analysis was performed in 42 DM and 60 Non-DM at >3 years follow up. Intrinsic renal cells were cultured and stimulated with diabetic conditions. These cytokines and fibronectin were measured in tubuloepithelial cells and podocytes. Results: Baseline plasma CCL18 and MIF predicted a decline in GFR in DM at >18 months but not at >3 years. Cytokine production varies over time with significant correlations at baseline that are not maintained. Cytokines correlate differently with GFR, ACR/UPCR in DM versus Non-DM proteinuric renal diseases. Plasma and serum cytokine levels correlated significantly with no correlation between these and urinary levels. All intrinsic renal cells were able to produce MIF, MCP-1 and CCL18 following stimulation. The interaction of these cytokines and their effects on fibronectin vary in diabetic conditions and following recombinant cytokine stimulation. The diabetic environment appears to orchestrate cytokine signals according to cell type. Conclusion: These results suggest cytokines may play a key role in the pathogenesis and or progression of DN. The clinical study suggests cytokines may predict progression; however, larger studies are needed with samples taken at different time points.
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Doernberg, Sarah Beth. "Macrophage Migration Inhibitory Factor Polymorphisms and Invasive Streptoccus Pneumoniae Infections." Yale University, 2006. http://ymtdl.med.yale.edu/theses/available/etd-06272006-110639/.
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Streptococcus pneumoniae[italicized everytime] (S. pneumoniae) causes a spectrum of disease severity, and human host factors likely play a role in this variation. One candidate factor is macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine and upstream regulator of innate immunity. The MIF[italicized when not in parenthesis] promoter contains two functional polymorphisms, a tetranucleotide (CATT) repeat such that MIF expression increases with repeat number from 5-8 and a single nucleotide polymorphism (SNP) leading to a G-to-C transition, which results in increased MIF expression in cell line reporter assays. Emerging data suggest an association between high-expression MIF alleles and inflammatory disease. This study comprised two parts. For the in vitro portion, we hypothesized that peripheral blood monocytic cells (pBMCs) cultured from healthy individuals with low-expressing MIF genotypes (5-CATT alleles or SNP-GG) would have lower MIF content and release than those from individuals with high-expressing MIF genotypes (7-CATT or SNP-C alleles). For the in vivo study, we hypothesized that individuals with low-expressing MIF genotypes would have less severe systemic inflammatory responses than individuals with high-expressing MIF genotypes in response to S. pneumoniae infection. Blood samples and chart findings were collected prospectively at three Connecticut hospitals from 30 inpatients with documented invasive S. pneumoniae infections. Genomic DNA was isolated from host blood, amplified, and genotyped using fragment analysis (CATT repeat) and allelic discrimination (SNP) methods. Fishers exact tests were used to compare genotypes and disease severity. For the in vitro experiments, there were no differences observed in serum MIF levels or MIF content or release from pBMCs based on MIF genotype. In the cohort of patients infected with S. pneumoniae, serum MIF levels among enrolled subjects were significantly higher than the reported normal values, but levels did not vary with genotype or disease severity. The SNP genotype was not correlated with disease severity or occurrence of meningitis. The CATT genotype did not correlate significantly with disease severity or occurrence of meningitis, although there was a trend suggesting an association between the 7-CATT allele and meningitis (p = 0.1188, 8% without meningitis had a 7-CATT allele vs. 40% with meningitis). More patient samples will need to be analyzed in order to definitively elucidate the role of MIF genetics in infection with S. pneumoniae
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Zis, Odysseas Takis. "The role of the macrophage migration inhibitory factor in stroke." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/24453.
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The macrophage migration inhibitory factor (MIF) is a 12kDa cytokine with pro-inflammatory properties. Initially characterized as a lymphocyte-secreted factor which inhibits macrophage migration in vitro, MIF has emerged as a multi-faceted cytokine involved in many processes, including cellular responses to ischemia/reperfusion injury in the heart. The main objective of this thesis was to determine whether human MIF expression is induced following cerebral ischemia, the underlying mechanism by which MIF expression is regulated under stroke conditions and its role therein. Previous studies have shown that MIF expression and release from cells is induced during hypoxia. However, the underlying mechanism is not clear. To examine whether the induction of MIF gene expression was mediated by its transcriptional upregulation, the human MIF gene promoter was cloned and a luciferase assay was used to determine the presence of a hypoxia responsive region in the human MIF promoter. The presence of a functional HIF-1α binding site was demonstrated using an electrophoretic mobility shift assay (EMSA). The results showed that upregulation of MIF gene expression under stroke is mediated by the effect of hypoxia on an HRE in MIF gene promoter. MIF has been shown to protect cells from ischemia and oxidative stress-induced cell death. To determine whether MIF has a similar protective effect on neurons, rat primary cortical neurons were cultured and subjected to either oxygen-glucose deprivation or treatment with hydrogen peroxide. MIF significantly reduced both OGD and H2O2-induced cell death. The expression of MIF in human brain has not been characterized. To determine whether the expression of MIF in human brain is altered following ischemia, brain sections from 10 stroke patients were immunostained with an antibody against MIF. Blood vessel endothelial cells in the peri-infarct region of ischemic brain displayed strong MIF immunoreactivity. Normal brain endothelium showed no MIF immunoreactivity. To understand the consequence of increased MIF expression by endothelial cells following stroke, the adhesion of human monocytes to human brain endothelial cells exposed to MIF was evaluated in vitro. MIF suppressed the monocyte adhesion to endothelial cells. The findings presented here are the first to suggest a role for MIF in cerebral ischemia.
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Bhavsar, Parag Jayprakash. "The role of Vav proteins in macrophage morphology and migration." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444025/.
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The Rho family GTPases are key signalling components that regulate the cytoskeleton and adhesion during cell migration. The Vav family of proteins act as guanine nucleotide exchange factors for several Rho GTPases. There are three isoforms of Vav expressed in mammalian cells: Vav1, the expression of which is largely restricted to haematopoietic cells, Vav2 and Vav3. In this study the role of Vav proteins in macrophage migration has been investigated using macrophages derived from mice lacking one or all three Vav isoforms. Cell migration and morphology were not significantly affected when single isoforms of Vav were absent from macrophages. However macrophages lacking all three isoforms adopted an elongated morphology in culture, which resulted in more persistent cell migration. Vav proteins were not required for chemotaxis to the macrophage chemo-attractant, colony-stimulating factor-1 (CSF-1). Vav proteins were also not required for CSF-1-stimulated Rac1 activation or Rac-mediated cytoskeletal reorganization in response to CSF-1. However, in response to CSF-1 stimulation Vav1 and Vav3 were phosphorylated on tyrosine residues, which has previously been shown to regulate their GEF catalytic activity. Macrophages lacking all three Vav proteins were defective in spreading upon adhesion to both glass and plastic. The defect correlated with reduced activation of Rac1 and RhoA, and a reduction in the activation of Erk1/2 and phosphorylation of paxillin in response to adhesion. Vav proteins are therefore not required for directed macrophage migration to the chemo-attractant CSF-1, but have an important role in adhesion-dependent signalling and are needed to maintain normal macrophage migration and morphology.
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Russell, Kirsty. "The role of macrophage migration inhibitory factor in airways disease." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/23917.
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Chronic obstructive pulmonary disease (COPD) and severe asthma are progressive chronic inflammatory diseases of the airways. Both diseases are characterised by airflow limitation and share some pulmonary symptoms. However they have distinct inflammatory cell signatures and differ in response to corticosteroid (CS) treatment. Most asthmatic patients control their disease with CS, with a few showing a relative CS resistance; however COPD patients show little or no improvement with CS and are CS insensitive. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator whose function is yet to be fully elucidated. MIF has been shown to counter-act the immunosuppressive action of CS. MIF is elevated in chronic diseases such as asthma and atherosclerosis. The role of MIF in COPD has not been investigated and its role in asthma is not fully understood. MIF inhibition attenuated ozone-induced airway inflammation and lung function in vivo but did not affect CS sensitivity. MIF expression did not vary between stable COPD patients and controls. Pro-inflammatory effects of MIF were investigated in THP-1 monocytes and primary cells. There was no clear role for MIF in LPS-induced inflammation. MIF modulated the transactivation functions of CS in THP-1 cells. Finally I took an unbiased approach to generate new hypotheses for MIF function using proteomic and transcriptomic techniques. The RIG-I-like pathway was identified by proteomics as a novel target pathway and was investigated in THP-1 cells and human BAL macrophage samples following viral infection. The role of MIF in airway inflammation remains unclear and results demonstrated here show MIF function does not necessarily translate from mouse to humans. MIF does not seem to have a role in the inflammation of stable disease. The proteomic data suggests that the association between viral infection, MIF and CS in regulating CS sensitivity in COPD and severe asthma should be investigated.
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Kithcart, Aaron P. "Macrophage migration inhibitor factor a key mediator of inflammatory disease /." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view.cgi?acc%5Fnum=osu1244077146.
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Kithcart, Aaron. "Macrophage Migration Inhibitory Factor: A Key Mediator of Inflammatory Disease." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1244077146.
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Van, Law Heather. "Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms in Vitreoretinal Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523296832882977.
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Chan, Hiu-man. "The roles of macrophage migration inhibitory factor in human neuroblastoma development." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38573945.
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Sommerville, Caroline. "Biochemical and immunological characterisation of Toxoplasma gondii macrophage migration inhibitory factor." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14468.
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Chan, Hiu-man, and 陳曉雯. "The roles of macrophage migration inhibitory factor in human neuroblastoma development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38573945.
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Schlander, Corinna. "Die Rolle von Macrophage Migration Inhibitory Factor (MIF) bei der malignen Transformation." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-72666.
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West, Peter William. "The regulation of Toll-like receptor signalling by macrophage migration inhibitory factor." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505343.
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Toll-like receptors (TLRs) fonn a vital part of the innate immune response to infection through the recognition of diverse molecular patterns leading to the generation of an inflammatory reaction. The resulting cytokines act on both tissue and immune cells to coordinate the response to infection. Cytokine networks also play an important role in the modulation of an increasing number of diseases which we now understand to have an inflammatory basis. TLR activation has been implicated in both chronic and acute diseases, and understanding and modulation of these responses may be central to th'e manageinent of inflammatory disease. This thesis investigates the impact of an enigmatic early response cytokine macrophage migration inhibitory factor on the TLR response of human cells. I have shown that the role ofMIF as an inflammatory cytokine is not clear-cut. Recombinant MIF failed to induce a significant inflammatory response from either a monocytic THP-l cell line or primary human monocytes. Furthennore, it failed to modulate the dexamethasone induced suppression of TLR induced cytokine release, a classically described activity of MIF. In keeping with these observations, anti-MIF antibodies did not modulate the LPS induced cytokine release of monocytes or monocytelHUVEC cocultures, which suggests that MIF may not act as a classical autocrine cytokine. I have demonstrated using a specific, cell-penneable MIF antagonist, known as ISO-I, and MIF siRNA, that MIF modulated specific arms of the TLR response leading to the activation of mitogen activated protein kinases (MAPKs) in monocytic cells. Cell-type spe~ific downstream effects on cytokine production were also seen. ISO-l potentiated LPS induced p38 phosphorylation and TNFa release from THP-I cells. Conversely, in primary monocytes, TNFa and CXCL8 production in response to LPS was significantly inhibited by both ISO-I and MIF siRNA, whilst TNFa but not CXCL8 production was maintained in response to TLR2 activation. LPS induced cytokine release from MDMs was unaffected by :NIIF inhibition. During the course of this thesis I have also observed differences in TLR2 induced inflammatory reactions in primary monocytes. This observation was explored further. These data suggest that whilst targeting MIF may be a useful therapeutic axis in disease, the roles of MIF are not straightforward. Further work will be needed to fully address the roles of this molecule in human biology.
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Trivedi-Parmar, Vinay. "Synthesis and Optimization of Non-Phenolic Inhibitors of Macrophage Migration Inhibitory Factor." Thesis, Yale University, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=13851921.
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Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and an upstream regulator of inflammation and cell proliferation. Interestingly, MIF is also an enzyme that functions as a keto-enol tautomerase, though this function is believed to be vestigial in humans. Implicated in the pathogenesis of multiple infectious and autoimmune diseases, including rheumatoid arthritis and cancer, MIF has emerged as an attractive drug target, with the tautomerase active site serving as a convenient binding pocket for small molecule inhibitors. Most MIF inhibitors include a phenol ring, which forms an essential hydrogen bond with an asparagine residue at the back of the binding pocket. While phenol is not an uncommon moiety in approved dugs, it is particularly susceptible to rapid phase 11 metabolic processes and excretion from biological systems, resulting in low oral bioavailability and short half-life. Therefore, potent non-phenolic MIF inhibitors are desirable. Two series of MIF inhibitors lacking the commonly employed phenol group were pursued and are described in this thesis.
The first was a series of benzoxazolone inhibitors. Attempts at lead optimization were stymied by sensitivity of tautomerase assay results to protein source and incubation conditions, inconsistencies between molecular modeling studies and experimental activity data, and the inability to obtain a crystal structure of the protein–inhibitor complex. A binding mode could not be resolved for the scaffold, preventing a rational, structure-based approach to drug development. Nevertheless, a methodical medicinal chemistry strategy was employed to elaborate the structure-activity relationships (SAR) of the series and discover potent inhbitors. A circa 5 µM inhibitor was obtained, but when further attempts to optimize the series proved ineffective, attention was turned to a new scaffold.
The second series of MIF inhibitors pursued involved bioisosteric replacement of phenol with a pyrazole, which is capable of forming dual hydrogen bonds with the asparagine residue at the back of the binding pocket. From a 113-µM virtual screening hit, a structure-based, computer-aided lead optimization strategy was employed. X-ray crystal structures of MIF-inhibitor complexes and molecular modeling results guided effective selection and placement of substituents on the scaffold. Methodical derivitization and expansion of the scaffold to include auxiliary aryl functionality near the rim of the binding pocket and recognition of the benefit of pyrazole fluorination were essential breakthroughs in optimizing this series, resulting in inhibitors with potencies around 60-70 nm. From a metabolic perspective, bioisosteric replacement of a salt bridge-forming carboxylate group on the scaffold with a pharmacologically favorable sulfonamide was found to be well tolerated. Additionally, modification of the solvent-exposed region of the scaffold with solubilizing groups was shown to improve aqueous solubility without affecting activity. The pyrazoles are the only the second series of MIF inhibitors to be optimized from an initial screening hit to give inhibitors with nanomolar potency. With their high potencies and expected favorable metabolism, compounds in this series have the potential to be developed into true MIF-directed therapeutics.
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Michelet, Claire. "Analyse évolutive et fonctionnelle des Macrophage Migration Inhibitory Factors chez les eucaryotes." Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4109/document.
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Les cytokines MIFs (Macrophage Migration Inhibitory Factor) sont des protéines multifonctionnelles qui, chez les mammifères, interviennent dans plusieurs processus majeurs tels que le contrôle du cycle et de la mobilité cellulaire, l’activation de la réponse immunitaire et l’inhibition de l’apoptose. Des travaux récents montrent que les protéines MIFs peuvent également jouer un rôle majeur dans l’immunité des invertébrés, et être utilisées par des organismes parasites d’animaux ou de végétaux pour inhiber les défenses de leurs hôtes respectifs, ce qui soulève la question de leur diversité, de leur histoire évolutive et des potentielles différences fonctionnelles. L’objectif général de ce travail de thèse était d’explorer la diversité et l’histoire évolutive des protéines MIFs à une échelle trans-règne, puis de rechercher leurs éventuelles différences fonctionnelles, en se focalisant sur les systèmes plantes-pathogènes. Nous avons tout d’abord identifié les MIFs chez 803 espèces de plantes, champignons, protistes, et métazoaires, et analysé leur présence/absence et histoire évolutive en fonction des taxa, de l’écologie et du mode de vie (libre ou parasitaire) des espèces. Nous avons montré que l’histoire évolutive des MIFs, chez les eucaryotes, est complexe et implique des duplications ancestrales ainsi que des pertes multiples ou des re-duplications récentes. Les plantes (espèces libres autotrophes) et les parasites de plantes (autres que champignons) possèdent un nombre médian de trois MIFs, alors que les espèces hétérotrophes et les parasites d’animaux ont un nombre de MIF plus faible et/ou plus variable. De plus, les protéines MIFs semblent essentielles et fortement conservées, avec de nombreux résidus sous sélection purifiante, chez certains groupes comme les plantes, alors que dans d’autres groupes, elles semblent facultatives (e.g. champignons) ou présentes en plusieurs copies divergentes (e.g. nématodes, insectes), ce qui suggère de potentielles néofonctionalisations. Nous avons ensuite analysé l’effet des protéines MIFs de plusieurs espèces sur la mort cellulaire en système végétal. Tous les organismes testés (plantes oomycètes, protozoaires, insectes et nématodes), y compris ceux n’ayant pas d’interaction avec les plantes, possèdent au moins une protéine MIF capable d’inhiber cette mort cellulaire. Cela suggère que l’inhibition de la mort cellulaire en plante ne correspond pas à une néofonctionalisation des MIFs de parasites de plantes, mais serait liée à des propriétés structurales et conservées des MIFs. Toutefois, aucun des paramètres étudiés (localisation subcellulaire) ou prédits in silico (présence de motifs, structures 3D, oligomérisation, modifications post-traductionnelles) ne semble lié à cette activité d’inhibition de la mort cellulaire. De futures études fonctionnelles poussées sont nécessaires à l’élucidation des relations structure/fonction de ces protéines complexesMacrophage migration inhibitory factors (MIF) are multifunctional proteins regulating major processes in mammals, including control of the cell cycle and migration, activation of innate immune responses, and prevention of p53-mediated apoptosis. MIF proteins also play a role in innate immunity of invertebrate organisms or serve as virulence factors in parasitic organisms, raising the question of their evolutionary history and of a putative differential evolution of structure/function relationships. The general aim of this PhD was to explore the diversity and evolutionary history of MIF proteins accross kingdoms, and to investigate their potential functional differences, with a special emphasis on host-parasite systems. We first performed a broad survey of MIF presence or absence and evolutionary relationships across 803 species of plants, fungi, protists, and animals, and explored a potential relation with the taxonomic status, the ecology, and the lifestyle of individual species. We show that MIF evolutionary history in eukaryotes is complex, involving ancestral duplications, multiple gene losses and recent clade-specific re-duplications. Of note, plants and plant parasites (other than fungi) harbour a median number of three MIFs, while heterotrophic and animal parasite species harbour a lower or/and variable MIF number. Intriguingly, MIFs seem to be essential and highly conserved with many sites under purifying selection in some kingdoms (e.g. plants), while in other kingdoms they appear more dispensable (e.g. in fungi) or present in several diverged variants (e.g. insects, nematodes), suggesting potential neofunctionalizations within the protein superfamily. We then analysed the effect of MIF proteins from selected species on plant cell death. All organisms tested (plant, oomycetes, protozoa, insects, and nematodes) including species that are not in interaction with plants, possess at least one MIF protein showing a significant cell death inhibitory effect. This suggests that plant cell death inhibition does not result from a neofunctionalization of MIF from plant-parasites, and is related to conserved structural features of MIF proteins. However, none of the parameters predicted in silico (sequence motifs, 3D structures, oligomerization, post-traductional modifications) appeared to be related to the cell death inhibitory activity. Future extensive functional studies are necessary to unravel the structure-function relationship of these evolutionarily and functionally complex proteins
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Jahns, Maximilian. "Über die Rolle von Macrophage Migration Inhibitory Factor(MIF) bei der murinen Hauttumorgenese." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-111241.
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Liu, Tiffany. "The role of macrophage chemoattractant signaling in cancer cell migration, metastasis and neovascularization." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p1476514.
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Pollak, Nils. "Die Rolle von MIF (macrophage migration inhibitory factor) in der Sepsis-induzierten Immunparalyse." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975902822.
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李晓 and Xiao Li. "Macrophage migration inhibitory factor and circulating progenitor cells: relevance and implications inperiodontal medicine." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45894267.
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