Dissertations / Theses on the topic 'Macrophage'
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Svensson, Ulf. "Macrophage activation by bacteria signalling to prostaglandin and cytokine responses /." Lund : Dept. of Medical & Physiological Chemistry, Lund University, 1994. http://books.google.com/books?id=sAhrAAAAMAAJ.
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Higuera, González Laura 1993. "Novel transcription regulators of tissue macrophages and alternative macrophage polarization." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/672702.
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Macrophages play crucial roles in the defense of the organism against a wide range of pathogens. Macrophages can rapidly adapt to perturbations in the microenvironment due to the existence of a network of transcription factors that modulates their responses. While transcription factors that regulate macrophage identity have been widely described in the past decades, the role of transcription regulators that fine-tune tissue macrophage responses in homeostasis and infection is starting to be elucidated.
Our group has previously identified transcription regulators of pro-inflammatory macrophage responses, and in the present work we have explored the function of novel transcription mechanisms that participate in the regulation of the homeostatic distribution of tissue macrophages and in anti-inflammatory macrophage responses. We have studied ontogenically different macrophage populations inhabiting different tissues and have characterized their transcription regulation. We have also compared the anti-inflammatory response of tissue macrophages and identified a specific transcriptional control of anti-inflammatory gene expression that depends on their ontogeny.Los macrófagos juegan un papel muy importante en la defensa del organismo frente a una amplia variedad de patógenos. Los macrófagos se adaptan rápidamente a las perturbaciones en el microambiente gracias a que existe una compleja red de factores de transcripción que modulan sus respuestas. En los últimos años se han identificado factores de transcripción que regulan la identidad de los macrófagos, sin embargo, apenas se está comenzando a conocer la importancia de otros factores de transcripción que permiten adaptar la respuesta de los macrófagos, tanto en condiciones homeostáticas como frente a infecciones. Anteriormente nuestro grupo identificó reguladores transcripcionales de las respuestas pro-inflamatorias de los macrófagos, y en este trabajo hemos explorado la función de nuevos mecanismos reguladores que participan en la regulación de la distribución de los macrófagos en homeostasis, así como en las respuestas anti-inflamatorias de los macrófagos. Hemos estudiado poblaciones de macrófagos con diferentes ontogenias que habitan dentro de los tejidos y hemos caracterizado su regulación transcripcional. Además, hemos comparado la respuesta anti-inflamatoria de los diferentes macrófagos tisulares y así hemos identificado que existe un mecanismo transcripcional específico que controla la expresión de genes anti-inflamatorios según el origen del macrófago.
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Tabata, Yasuhiko. "Macrophage phagocytosis of polymer microspheres and antitumor activation of macrophages." Kyoto University, 1987. http://hdl.handle.net/2433/74704.
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Raborn, Erinn Shenee. "Cannabinoid Modulation of Chemotaxis of Macrophages and Macrophage-like Cells." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1333.
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Adler, Heiko. "Fetal bovine bone marrow-derived macrophages : a model for studying basic aspects of macrophage biology and pathogen-macrophage interaction in cattle /." [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Grand-Perret, Thierry A. R. "Induction d'une activité anti-tumorale chez les macrophages péritonéaux murins." Paris 11, 1986. http://www.theses.fr/1986PA112301.
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Di, Maggio Paula. "Dietary lipids and inflammation : chylomicron remnants suppress pro-inflammatory pathways and activate antioxidant defence mechanisms in human macrophages." Thesis, Royal Veterinary College (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618287.
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Soe-Lin, Shan. "Macrophage iron recycling." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66717.
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In an absurd twist of nature, the physiological role of iron is paradoxical. Iron is the most abundant element found on Earth and yet is insoluble under physiological conditions. Furthermore, life is not possible without iron; iron is indispensible for life, as it is a vital co-factor for essential enzymes due to its unique redox abilities. And yet, high concentrations of iron lead to the formation of reactive oxygen species and are toxic. Consequently, living creatures have evolved ingenious strategies for acquiring and managing otherwise insoluble iron atoms, and for tightly regulating its levels within the organism. The majority of bodily iron in humans is contained within the red blood cell (RBC) mass, as a component of hemoglobin. RBCs become more damaged and less deformable as they age, and at the end of their 120 day lifespan, senescent RBCs are engulfed by macrophages of the reticuloendothelial system of the liver and spleen. These specialized macrophages ingest 2 million RBCs/sec, catabolize the hemoglobin, and release the iron contained within to plasma transferrin for reincorporation into new RBCs within the bone marrow. It is remarkable how reticuloendothelial macrophages safely manage the enormous quantities of iron which would otherwise prove toxic to other cells. In my studies, I have examined the specific aspects of iron metabolism within these iron-handling macrophages. Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed only within the phagosomes of professional phagocytic cells such as macrophages and neutrophils. Nramp1 has since been found to be the gene responsible for conferring host resistance against intracellular pathogens. Mice deficient in Nramp1 have been found to be susceptible to infection with intracellular pathogens. Nramp1 is thought to confer protection by depleting the phagosome of divalent metals necessary for pathogenLa majorité du fer dans le corps humain est contenu dans la masse de globule rouge, en tant que composante de l'hémoglobine. Les GR deviennent plus endommagés et moins déformables en vieillissant, et à la fin de leurs durée de vie de 120 jours, les GR sénescents sont ingurgités par les macrophages du système réticuloendothélial du foie et de rate. Ces macrophages spécialisés ingèrent 2 millions de GR∕sec, catabolisent l'hémoglobine et relâche le fer qui y est contenu à la transferrine plasmatique pour permettre son réincorporation dans de nouveau GR dans la moelle épinière. C'est remarquable comment les macrophages réticuloendothéliaux gèrent de manière sécuritaire l'énorme quantité de fer qui serait sinon toxique pour les autres cellules. Dans mes recherches, j'ai examiné les aspects spécifiques du métabolisme du fer dans ces macrophages spécialisés dans sa manutention.La protéine associée à la résistance naturelle du macrophage (Nramp1) est un transporteur de métaux divalents exprimé seulement dans les phagosomes de cellules phagocytiques telle que les macrophages et les neutrophiles. Nramp1 a depuis été reconnu comme le gène responsable de conférer à l'hôte la résistance contre les pathogènes intracellulaires. Nramp 1 est présumé donner une protection en vidant le phagosome de métaux divalents nécessaires à la croissance de pathogènes.Au cours des recherches nous avons trouvé qu'en plus de jouer un rôle significatif dans la résistance de l'hôte, Nramp1 est aussi important pour la régularisation de l'homéostasie du fer. Nous avons remarqué que les macrophages sans Nramp1 sont incapables de recycler le fer (après l'erythrophagocytose in vitro) de manière aussi efficace que les macrophages qui ont le Nramp1 fonctionnel. On a ensuite observé les souris knockout et trouvé que les animaux sans Nramp1 ont une surdose progressive de fer en vieil
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Georges, George Tharwat. "Novel Characteristics of Murine Bone Marrow-Derived Macrophages and Human Macrophage-Like Cells." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/932.
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These studies provide evidence for novel properties of macrophages derived from bone marrow stem cells. In study 1, treatment of activated mouse bone marrow-derived macrophages (BMM) with either catecholamine synthesis inhibitors (α-methyl-para-tyrosine and fusaric acid) or the β2 adrenergic receptor antagonist ICI 118,551 demonstrated that BMM produce catecholamines. The catecholamines modulated macrophage cytokine production through autocrine actions on adrenergic receptors. In study II, undifferentiated human bone marrow cells were incubated in 30% mouse L929 fibroblast conditioned medium and generated adherent cells within three days. The cells were clearly identifiable as macrophages based on surface proteins and phagocytic activity but produced only low levels of the cytokines tumor necrosis factor-α and interleukin-lβ. Cytokine production did not increase in response to the bacterial endotoxin lipopolysaccharide (LPS). Generation of these macrophage-like cells was not repeatable with other samples of human bone marrow, but the cells continue to proliferate in cell culture and will be investigated further in future studies.
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Sobhani, Kimia. "Proteomic analysis of macrophage proinflammatory programmed cell death and macrophage activation /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8688.
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Awomoyi, Agnes Abiola Oluwatoyin. "Genetics of susceptibility to tuberculosis." Thesis, Open University, 2000. http://oro.open.ac.uk/58012/.
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Convincing evidence that activated macrophages play a critical role in control of mycobacterial diseases has been clearly established from animal and in-vitro studies. Macrophages produce a variety of molecules upon appropriate stimulation, which act in concert towards eventual killing of bacteria. People with SUb-optimal macrophage activation are more susceptible to infection with intracellular pathogens. My project aims to answer two questions relating to genetic regulation of macrophage activation in tuberculosis: do macrophage genes regulate microbial-induced responses and do macrophage genes influence susceptibility to tuberculosis? A whole blood assay was used to investigate IFN-y responsiveness in healthy individuals and those who develop tuberculosis in The Gambia. Cytokine responses to lipopolysaccaride (LPS), Lipoarabinomanan (LAM) and the enhancing effect of IFN-y on these stimulants were measured. LPS induced IL-l 0 levels was higher in recovered TB cases than in controls (p=0.02). LPS and LAM induced cytokines were highly correlated (p<0.0001) similarly, levels of IL-IB and TNF were highly correlated (P
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Davis, John Beresford. "The macrophage in atherogenesis." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.276341.
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Falck-Hansen, Mika André. "Macrophage regulation in atherosclerosis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29863.
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Atherosclerosis is the leading cause of cardiovascular disease, topping the mortality list in the United Kingdom and the rest of the world. Macrophage activation and polarisation are key steps in host defence and chronic inflammatory diseases, including atherosclerosis. The myeloid glycoprotein receptor CD200R1 belongs to a family of four isoforms and signals after binding to its cognate ligand, CD200. The CD200/CD200R1 interaction blocks pro-inflammatory cytokines and has never before been studied in atherosclerosis. My work has demonstrated that CD200R is weakly expressed in atherosclerotic lesions during disease progression and significantly down-regulated in secondary lymphoid organs. Moreover, changes in shear stress had no effect on the expression of CD200R in plaques. During the steady state, the expression of CD200R on circulating monocytes was highest on the CD11b+CD115+Ly6Cint subset, revealing a potential mechanism for regulation of maturing monocytes. In vitro studies demonstrated that CD200R expression is sensitive to M1 macrophage polarising cytokine IFN-γ and MyD88-dependent TLR ligands. In contrast, non-MyD88-dependent TLR3 signalling had no effect on its expression, supporting previous findings in the literature. Moreover, CD200R1 mRNA expression was induced on alternatively activated M2a macrophage subsets following IL-4 and IL-13 cytokine treatment, whereas oxLDL had no effect. Immunotherapy with CD200-Fc in ApoE-/- mice exerted no significant changes on lesion size and phenotype compared to controls after nine weeks. My findings indicate that the type of inflammatory stimulus may play a role in dictating the ability of myeloid cells to terminate their own activation via CD200/CD200R1 signalling. Hence, chronic inflammation may be promoted by reduced presence of inhibitory signals leading to sustained, unresolved inflammation. In summary, my work has revealed new insight into the regulation of the inhibitory CD200R pathway in atherosclerosis, the molecular signals that may affect the regulation of inflammation through CD200R and possible future therapeutic strategies.
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Dewhurst, Jennifer. "Macrophage subpopulations in COPD." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/macrophage-subpopulations-in-copd(e0e66fa4-ddff-4591-b785-edee74918539).html.
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Lung macrophage numbers are increased in Chronic Obstructive Pulmonary Disease (COPD). Macrophage subpopulations with differences in cell surface marker expression and function have been identified in sputum. The aim of this thesis was to investigate the role of lower airway macrophage subpopulations in COPD, focussing on their phenotype and function. Alveolar and interstitial cells from human lung resection tissue were isolated by perfusing the airways with saline. Interstitial cells were isolated by mechanically and enzymatically digesting perfused lung tissue. Alveolar and interstitial macrophages were negatively selected using a monocyte enrichment kit. Flow cytometry and PCR were used to identify and phenotype macrophage subpopulations. A flow cytometry based phagocytosis assay was used to characterise the function of macrophage subpopulations. Subpopulations of alveolar macrophages and interstitial macrophages were identified as “small macrophages” and “large macrophages” based on size and granularity. Small macrophages were further characterised as HLA-DRhigh, CD14high, CD38high, CD36high, CD206low. Large macrophages were characterised as HLA-DRlow, CD14low, CD38low, CD36low, CD206high. The percentage of large macrophages was reduced in the interstitium compared to alveolar macrophages, while the opposite pattern was observed for small macrophages (increased percentage in interstitium). No significant differences between the proportion of macrophage subpopulation from COPD patients and smokers have been observed. Large interstitial macrophages were 66% apoptotic. Small interstitial macrophages had high inflammatory potential but low phagocytic ability; small alveolar macrophages had intermediate inflammatory potential but high phagocytic ability; large alveolar macrophages had low inflammatory potential and low phagocytic ability. In addition the phenotype and function of large macrophages from COPD patients was sensitive to current smoking. I have shown phenotypically different subpopulations of alveolar and interstitial macrophages exist. The proportion of small and large macrophages varies between the interstitium and alveolar space. Small macrophages appear to polarised towards an inflammatory phenotype compared to large macrophages. Therefore targeting macrophages for COPD therapy should be tailored towards specific subpopulations.
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Davies, Luke C. "Control of macrophage homeostasis." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/112185/.
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Tissue resident macrophages are extremely heterogeneous, which reflects their unique microenvironments and tissue specific functions. They are a constituent of all tissues, and are involved in homeostatic processes and inflammatory disease. Recent studies have shown that select tissue resident macrophage populations, such as Langerhans cells of the skin and microglia of the brain, are able to self-renew independently from the bone marrow. This is contrary to the prevailing model macrophage origins, the ‘mononuclear phagocyte system’, which dictates that all macrophages are derived from bone marrow monocytes. The work carried out in this thesis investigated the self-renewing potential of peritoneal tissue resident macrophages, and its control. Several novel discoveries were made: i) peritoneal resident macrophages proliferate at low levels to maintain their numbers during homeostasis, at higher levels during neonatal growth, and undergo a burst in proliferation during acute inflammation to restore their depleted population; ii) renewal of peritoneal resident macrophages during an acute inflammatory episode was found to be independent from the bone marrow, and dependent upon macrophage colony stimulating factor, but importantly, not interleukin-4; iii) Monocyte-derived macrophages could also proliferate within an inflammatory lesion. Collectively, these observations challenge the dogma of the mononuclear phagocyte system: they demonstrate that in vascular tissues, tissue resident macrophages could self-renewal independently of monocytes, and that monocyte-derived cells are not terminally-differentiated. Additional work leading up to these studies implicated Gata6 as a peritoneal macrophage-specific transcription factor. In this thesis, Gata6 was found to be necessary for peritoneal macrophage phenotype, normal proliferation, euploidy, and normal responses to inflammation. In summary, these studies demonstrate not only are macrophages capable of self-renewal, but this is dependent upon discrete transcriptional control. Understanding the molecular controls of tissue macrophage heterogeneity and renewal could provide novel avenues for the therapeutic manipulation of their activities.
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Bouchareychas, Laura. "Implication des phagocytes mononuclées dans l'évolution de la plaque d'athérosclérose et relation avec l'homéostasie du cholestérol et des lipoprotéines." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066282/document.
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L'athérosclérose est un processus physiopathologique chronique impliqué dans la majorité des maladies cardio-vasculaires. Le développement des lésions d'athérosclérose est caractérisé par l'accumulation de lipides extra et intracellulaires dans la paroi artérielle à l'origine d'une forte réponse inflammatoire impliquant notamment les macrophages. Les macrophages sont considérés comme des acteurs clés dans le développement des plaques d'athérosclérose. En effet, de par leur capacité à métaboliser le cholestérol (captation, stockage, efflux), à réguler l'inflammation et à phagocyter les cellules apoptotiques, ils exercent des fonctions pro et/ou anti-athèrogènes qui peuvent être modulées à des fins thérapeutiques. Dans cette perspective, nous avons évalué le pouvoir thérapeutique des " macrophages protégés de l'apoptose " sur la progression des lésions d'athérosclérose constituées. Nous avons démontré que l'augmentation de la survie des macrophages permet de ralentir la progression des lésions, de stabiliser les lésions et de diminuer la cholestérolémie. Ces effets athéro-protecteurs sont attribués à l'augmentation des cellules de Kupffer et des monocytes Ly-6Clow en partie par leur capacité à produire de l'apolipoprotéine E. Nous montrons également que les cellules de Kupffer participent à la clairance des lipoprotéines pro-athérogènes. L'augmentation du pool d'apoE ainsi que l'augmentation des cellules de Kupffer permettent de diminuer la cholestérolémie et ainsi de diminuer la progression des lésionsAtherosclerosis represents a chronic pathophysiological process implicated in the majority of cardiovascular diseases. The development of atherosclerotic lesions is characterized by an accumulation of extra and intracellular lipids in the arterial wall at the origin of a strong inflammatory response involving macrophages.Macrophages are considered key actors in the development of atherosclerotic plaques. Indeed, because of their ability to metabolize cholesterol (capture, storage, efflux), to regulate inflammation and to phagocyte apoptotic cells, they exert pro and/or anti-atherogenic functions that may be modulated therapeutically. In this context, we evaluated the therapeutic potential of macrophages protected against apoptosis, on the progression of established atherosclerotic lesions.We have demonstrated that increased macrophage survival can slow down the progression of established lesions, stabilize lesion and reduce cholesterol levels. These athero-protective effects are attributed to the increase in Kupffer cells and Ly-6Clow monocytes partly due to their ability to produce apolipoprotein E. We also show that Kupffer cells are involved in the clearance of pro-atherogenic lipoproteins. The increase in ApoE pool and in Kupffer cells reduces cholesterol levels and thus lesion progression
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Lisowski, Zofia Maria. "Targeting the macrophage in equine post-operative ileus." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33191.
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Post-operative ileus (POI) is the functional inhibition of propulsive intestinal motility which is a frequent occurrence following abdominal surgery in the horse and in humans. Rodent and human-derived data have shown that manipulation-induced activation of the resident muscularis externa (ME) macrophages in the intestine contributes to the pathophysiology of the disease. Most studies of the disease, specifically in the horse, have focussed on identification of risk factors, descriptive studies of the disease or the assessment of the efficacy of various therapeutic and prophylactic interventions. As a result, the proposed pathogenesis of equine POI is largely reliant on the translation of data from rodent models. The aims of this thesis were to identify macrophage populations in the normal equine gastrointestinal tract (GIT) and to study equine macrophage activation by stimulating equine bone marrow-derived macrophages (eqBMDMs) with lipopolysaccharide (LPS) as a model for intestinal macrophage activation. Firstly, the normal population of macrophages in the equine GIT was determined. Using CD163 as an immunohistochemical marker for macrophages. CD163+ve cells were present in all tissue layers of the equine intestine: mucosa, submucosa, ME and serosa. CD163+ve cells were regularly distributed within the ME, with accumulations adjacent to the myenteric plexus, and therefore to intestinal motility effector cells such as neurons and the Interstitial Cells of Cajal. The differentiation and survival of intestinal macrophages depends upon signals from the macrophage colony-stimulating factor (CSF-1) receptor. LPS translocation from the gut lumen is thought to be a key activator of ME macrophages. To provide a model for gut macrophages, a protocol was optimised to produce pure populations of equine bone marrow-derived macrophages (eqBMDMs) by cultivation of equine bone marrow in CSF-1. Macrophage functionality was assessed using microscopy, flow cytometry and phagocytosis assays. EqBMDMs responded to LPS stimulation with increases in expression of positive control genes, tumour necrosis factor alpha (TNF-α) and Indoleamine 2,3-dioxygenase (IDO1). The same mRNA was subjected to transcriptomic (RNA-Seq) analysis. Differential gene expression and network cluster analysis demonstrated an inflammatory response characterised by the production of pro-inflammatory cytokines such as interleukin 1 beta (IL-1β) and interleukin 6 (IL-6). However, in contrast to rodent macrophages, eqBMDMs failed to produce nitric oxide in response to LPS, showing species-specific variation in innate immune biology. Using these data, we compared gene expression in normal equine intestine and in intestine from horses undergoing abdominal surgery for colic (abdominal pain). Horses undergoing abdominal surgery showed evidence of increased expression of IL-1β, IL-6 and TNF-α in the mucosa and ME when compared to control tissue. Horses with post-operative reflux (POR), a clinical sign of POI, had increased gene expression of IL-1β, IL-6 and TNF-α compared to horses that did not develop POR following abdominal surgery. These preliminary data suggest that there is macrophage activation within the ME of the intestine during abdominal surgery in the horse, and that a greater activation state is present in horses that subsequently develop POR. The final part of this study was to investigate the effect of a long-acting form of CSF- 1, an Fc fusion protein (CSF1-Fc), as a potential treatment for POI using a mouse model. This work, performed in collaboration with another research group, found that mice lacking the C-C chemokine receptor type 2 (CCR2) gene, which is required for monocyte recruitment into tissues, had a longer recovery period following intestinal manipulation (IM) than wild type (WT) mice. With the administration of CSF1-Fc, infiltration of neutrophils to the ME was reduced and the number of macrophages in the ME was increased in both WT and CCR2-/- mice following IM. Administration of CSF1-Fc in CCR2-/- mice improved recovery of gastrointestinal transit three days following IM, to the same extent as WT mice. Network cluster analysis and RT-qPCR of the ME revealed clusters of genes induced and downregulated by CSF1-Fc, with increased expression of anti-inflammatory and pro-resolving genes after IM in WT and CCR2-/- mice following treatment with CSF1-Fc.
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Alhanghari, Mofeda Abdussalam. "The Anti-Apoptotic Effect of HSV-1 ON Murine Macrophages: RAW 246.7Murine Macrophage Cell Line." Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1472747895.
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Lévêque, Manuella. "Résolution de l'inflammation - infection dans les macrophages de patients atteints de mucoviscidose : impact de la membrane." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B041/document.
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Les macrophages sont en première ligne de la défense innée et jouent un rôle important dans l’initiation de la réponse immunitaire puisque régulant l’inflammation et permettant la clairance des pathogènes. Dans la mucoviscidose, ces phénomènes sont exacerbés et deviennent chronique sans pouvoir être résolus. Les objectifs de cette thèse ont été de déterminer des cibles potentielles responsables des altérations du macrophage dans la mucoviscidose. Dans le contexte inflammatoire, la forme soluble du CD14 (sCD14), dont la sécrétion est augmentée par les macrophages de patients atteints de la mucoviscidose, est caractérisé comme un DAMP puisqu’il contribue à l’entretien de l’inflammation au niveau tissulaire. Dans le contexte infectieux, l’activité de TRPV2, impliqué dans la phagocytose, est altérée. Dans la mucoviscidose, l’inflammation et l’infection sont aussi intimement liées par l’intermédiaire d’une altération des microstructures de la membrane plasmique impliquée dans la production du sCD14 et dans le processus de phagocytose. En conclusion, les modifications des fonctions du macrophage affaiblissent la défense innée des patients atteints de mucoviscidose et peuvent être impliqués dans la progression de la maladie. Par conséquent, les interventions visant à réduire l’inflammation et l’infection pourraient être bénéfiques afin de préserver la fonction pulmonaire des patients. Ainsi, les approches thérapeutiques visant à corriger les dysfonctions du macrophage de patients atteints de mucoviscidose pourrait fournir une meilleure résolution de l'infection et l'inflammationMacrophages play a significant role in the initiating stages of immune responses regulating inflammation and clearance of the pathogens. In cystic fibrosis, inability of the macrophage to act as a suppressor cell leading to chronic inflammation/infection cannot be resolved. The aims of this work was to find new targets responsible for alterations in cystic fibrosis macrophages. Regarding inflammation, the soluble form of CD14 (sCD14), find overproduced by cystic fibrosis macrophages, is characterized to be a DAMP as it contributes for maintenance of inflammation in tissues. Regarding infection, the activity of TRPV2, involved in phagocytic capacity of macrophage, is impaired. In cystic fibrosis, inflammation and infection were closely linked to the alteration of the plasma membrane microstructures involved in the production of sCD14 and in the phagocytosis process. In conclusion, the alterations of macrophage weaken innate defense of cystic fibrosis patients and may be involved in cystic fibrosis disease progression and lung damage. Consequently, interventions aimed to reduce ongoing infection and destructive inflammatory response may be beneficial in order to preserve their lung function. In this way, therapeutic approaches aimed to correct cystic fibrosis macrophages dysfunctions might provide improved resolution of infection and inflammation
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Foo, Suan Sin. "Deciphering the Role of Macrophage Subsets and Macrophage-Derived Factors During Arthrogenic Alphaviral Infection." Thesis, Griffith University, 2015. http://hdl.handle.net/10072/365249.
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The current situation of global warming has a serious impact on the control of arthropod-borne infectious diseases. Climate change has led to an increase in conducive breeding habitats for mosquitoes. This change in climate has contributed to the widespread distribution of mosquito-transmitted arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV). RRV is currently endemic to Australia and Papua New Guinea, while CHIKV causes global outbreaks. The recent CHIKV outbreak in the Americas has taken the world by surprise and has affected more than 1 million individuals as of early 2015. To date, there are no specific therapeutics strategies available for the treatment of alphaviral diseases, largely due to the ill-defined innate immune responses elicited by these viruses. This thesis describes new insights into the alphavirus-elicited immune response at the cellular and molecular levels using in vitro, in vivo and ex vivo experimental approaches. In these studies, we identified the differential role of macrophages in modulating the RRV disease progression through an atypical IL-10-dependent M1/M2 polarisation of inflammatory monocytes. RRV-induced differentiation of M1 macrophages triggered the pathogenic inflammatory processes giving rise to the onset of disease, while M2 macrophages were shown to play a protective role.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Institute for Glycomics
Science, Environment, Engineering and Technology
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Merlin, Johanna. "Étude de l’influence de la glutaminolyse des macrophages dans les maladies cardio-métaboliques." Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://theses.univ-cotedazur.fr/2020COAZ6016.
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Les maladies chroniques inflammatoires telles que l’obésité ou l’athérosclérose constituent un problème majeur de santé publique dans les pays occidentaux. Il est désormais bien établi que les cellules immunitaires, et en particulier les macrophages, jouent un rôle essentiel dans l’initiation et la progression de ces maladies métaboliques. En effet, les macrophages résidents au sein des tissus contrôlent leur homéostasie comme par exemple l’expansion du tissu adipeux viscéral ou la thermogenèse du tissu adipeux brun. Cependant, les mécanismes restent mal compris. L’immuno-métabolisme est un nouveau domaine de recherche qui illustre l’adaptabilité des macrophages à leur environnement nutritionnel pour le maintien de leurs fonctions. Nous nous sommes ainsi intéressés au rôle de la glutamine dans l’homéostasie des macrophages et son impact sur l’obésité et l’athérosclérose. Pour cela, nous avons génétiquement supprimé l’enzyme limitante hydrolysant la glutamine en glutamate, appelée glutaminase 1 (Gls1), spécifiquement au sein des cellules myéloïdes. Dans notre première étude, nos données démontrent que l’absence de Gls1 dans les cellules myéloïdes conduit à une intolérance au glucose sous régime riche en graisses, associée à une diminution des niveaux de norépinephrine dans le tissu adipeux brun conduisant alors à un défaut de thermogenèse. Nos résultats mettent en évidence une diminution de l’adhésion des macrophages de la moelle épinière aux neurones glutamatergiques et diminuant ainsi l’activation de ces derniers. Notre étude démontre donc le rôle de la glutaminolyse des macrophages dans le contrôle du tonus sympathique des tissus adipeux thermogéniques. Dans un second temps nous avons étudié l’impact la glutaminolyse des cellules myéloïdes sur le développement de l’athérosclérose. L’invalidation de la glutaminolyse des cellules myéloïdes entraîne une augmentation de la surface de la plaque athéromateuse. En particulier, nous avons pu observer une augmentation de la nécrose des plaques suggérant une nouvelle fonction de la glutaminolyse des macrophages. Nous avons également pu valider cette association dans des plaques athéromateuses humaines. Bien que la déficience en Gls1 dans les macrophages n’altère pas leur survie, nous avons pu mettre en évidence un rôle clé de cette voie dans le processus d’efférocytose. L’analyse des mécanismes en aval a révélé une altération de la polarisation alternative des macrophages chez ces souris associée à une reprogrammation du métabolisme mitochondrial. La modulation de ces voies conduit à une baisse d’activité de Rac1 expliquant ainsi le défaut d’efférocytose. Ainsi, notre seconde étude identifie la glutaminolyse des cellules myéloïdes comme un acteur essentiel dans le développement des maladies cardiovasculairesChronic inflammatory diseases such as obesity or atherosclerosis are a major public health concern in the western countries. It is now well established that immune cells, and in particular macrophages, play a critical role in the initiation and progression of cardiometabolic diseases. Indeed, tissue resident macrophages control tissue homeostasis such as visceral adipose tissue expansion and brown adipose tissue thermogenesis. However, the underlying mechanisms remain unknown. Immuno-metabolism is a new research area that illustrates macrophage adaptability to their nutritional environment for their function maintenance. We therefore looked at the role of glutamine in macrophage homeostasis and its impact on obesity and atherosclerosis. Therefore, we genetically abolished the limiting enzyme hydrolyzing glutamine to glutamate, called glutaminase 1 (Gls1), specifically in myeloid cells.In our first study, our data demonstrate that Gls1 deficiency in myeloid cells leads to glucose intolerance on a high-fat diet. This is associated with a decrease in norepinephrine levels in brown adipose tissue leading to defective thermogenesis. Our results highlight a decrease in spinal cord macrophage adhesion to glutamatergic neurons leading therefore to a decrease in neuron activation. Thus, our study demonstrates the role of macrophage glutaminolysis in controlling the sympathetic tone of thermogenic adipose tissue.Secondly, we studied the impact of myeloid cell glutaminolysis on atherosclerosis development. Glutaminolysis invalidation in myeloid cells leads to an increase atherosclerotic plaque area. In particular, we observed an increase in plaque necrosis suggesting a new function for macrophage glutaminolysis. We also validated this association in human atheromatous plaques. Although Gls1 deficiency in macrophages does not affect their survival, we showed a key role of this pathway in efferocytosis. Further analyses of the downstream mechanisms revealed an alteration in macrophage alternative polarization associated with mitochondrial metabolism reprogramming. Modulation of these pathways leads to a drop in Rac1 activity, thus explaining the efferocytosis defect. Therefore, our second study identifies myeloid cell glutaminolysis as an essential actor in atherosclerosis development
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Reichard, Adam Craig. "The Effects of HSV-1 Challenge on Polarized Murine Macrophages: an In Vitro Model Using the J774A.1 Murine Macrophage Cell Line." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1343411395.
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Kluftinger, Janet Louise. "Macrophage interaction with Pseudomonas aeruginosa." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/29129.
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The interactions of macrophages with Pseudomonas aeruginosa were studied. Five monoclonal antibodies specific for porin protein F were tested for their ability to opsonize P. aeruginosa for complement-independent phagocytosis by unelicited mouse peritoneal macrophages, human peripheral blood monocytes and mouse macrophage cell line P388[sub D1]. All five antibodies significantly increased the level of bacterial uptake over that obtained with the non-opsonic controls. The relative effectiveness of the different antibodies was approximately the same in all cell types indicating that the P388[sub D1] cells can be used as a model for normal macrophages. Of the four monoclonal antibodies directed against similar epitopes of protein F, the three IgGl monoclonal antibodies were substantially more opsonic than the one IgG2a isotype.
P. aeruginosa cytotoxin and periplasmic contents caused a significant reduction in antibody-mediated phagocytosis of P. aeruginosa. Phagocytosis was restored upon pre-incubation with anti-cytotoxin serum. Both cytotoxin and periplasmic contents caused depolarization of the P388[sub D1] cell membrane, as demonstrated using a polarization-sensitive fluorescent probe. These data indicated that P. aeruginosa cytotoxin was localized in the periplasm and had the potential to inhibit macrophage-mediated phagocytosis, possibly by perturbing ion gradients across the macrophage plasma membrane. Monoclonal antibodies directed against protein F were also capable of enhancing phagocytosis of in vivo-grown P. aeruginosa. P. aeruginosa cells taken directly from the in vivo growth system were significantly more susceptible to macrophage phagocytosis than were the same cells after being washed in buffer. The phagocytosis-promoting factor could be isolated from the supernatant of in vivo-grown bacteria and was determined to be fibronectin. Data indicated that promotion by fibronectin of non-opsonic phagocytosis was mediated by direct activation of the macrophages. The tetrapeptide arginine-glycine-aspartate-serine in the eukaryotic cell binding domain of fibronectin was demonstrated to be the macrophage-activating region. Phagocytosis of a mutant P. aeruginosa strain lacking surface pili could not be enhanced by fibronectin. Furthermore, exogenously added Pseudomonas pili was capable of abrogating the enhanced phagocytosis of the wild type strain observed with fibronectin-activated macrophages. It was concluded that Pseudomonas pili were the bacterial ligands required for attachment to fibronectin-activated macrophages in the initial stages of non-opsonic phagocytosis.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Truman, Lucy. "Macrophage chemotaxis to apoptotic cells." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29404.
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The CD14 knockout mouse (CD14-/-) was observed to have increased numbers of free apoptotic cells in the thymus. It was hypothesised that this was due to a defect in macrophage clearance of dying cells. In vitro assays revealed that macrophages from the CD14-/- mouse had a partial defect in the phagocytosis of apoptotic cells. Clearance also involves macrophage movement towards the apoptotic corpse. Therefore, it was hypothesised that, in addition to a phagocytosis defect, CD14-/- had impaired chemotaxis to apoptotic cells. An in vitro transmigration assay was developed using the B-cell line “Mutu” as a source of apoptotic cells. In this assay, monocytes and macrophages, but not neutrophils, migrated preferentially to apoptotic Mutu, and chernotaxis correlated to phosphatidylserine exposure on apoptotic cells. Chemotaxis was abolished when Mutu were transfected with the anti-apoptotic protein bcl-2. Although CD14 was up regulated on the surface of the migrating macrophages, experiments with knockout cells revealed that chemotaxis did not require either CD14 or the scavenger receptor CD36. Experiments using a viral chemokine antagonist (vMIPII) suggested that fractalkine (CX3CL1) was a candidate chemokine released from dying cells. Fractalkine was expressed by apoptotic cells and in chemotaxis assays CX3CL1 competitively inhibited macrophage migration to apoptotic cells but not to CCL5 (RANTES). Monoclonal antibodies that blocked the chemokine domain of CX3CL1 also inhibited macrophage chemotaxis to apoptotic cells. This is the first demonstration of the involvement of a known chemokine receptor in the clearance of apoptotic cells. In this novel process, cells dying by apoptosis release fractalkine that recruits macrophages primed to efficiently engulf the cell corpse.
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Heasman, Sarah Jane. "Glucocorticoid modulation of macrophage function." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29146.
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In this thesis, I have examined the effects of glucocorticoid-treatment of peripheral blood monocytes which has previously been demonstrated to markedly augment phagocytic capacity for apoptotic cells, an effect which may contribute to anti-inflammatory actions of glucocorticoids. Within the inflammatory site, the cytokine environment governs the differentiation and function of infiltrating leukocytes. I have investigated the effects of combinatorial treatment of monocytes with the principal Th1 and Th2 cytokines, IFN-γ and IL-4. I have demonstrated that whilst glucocorticoids exert a dominant effect over those of IFN-γ in terms of cell morphology and cell surface receptor expression, glucocorticoid-augmented phagocytosis of apoptotic neutrophils is inhibited by IFN-γ. These findings suggest that the effectiveness of glucocorticoids in promoting a highly phagocytic macrophage phenotype is crucially dependent on the cytokine milieu at inflammatory sites. Cellular migration is an important determinant for the initiation of inflammatory responses and for the resolution phase, where macrophages migrate to draining lymph nodes. My results provide evidence for an alteration in the adhesion and migration of macrophages following glucocorticoid treatment. I have demonstrated changes in cytoskeletal organisation and assembly/engagement of Rho family GTPase signalling pathways. These changes may influence macrophage migration patterns that are important for the progression of inflammatory responses. Together, the studies presented in this thesis suggest that glucocorticoids exert profound effects upon macrophage cytoskeletal organisation that influences both phagocytosis and migration and may also cause a switch in apoptotic cell recognition mechanisms.
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McMurray, Heather Forbes. "Macrophage growth factors in atherogenesis." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306460.
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Rossi, B. C. "Macrophage function in African trypanosomiasis." Thesis, Brunel University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373784.
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McCarthy, Sean Patrick. "Studies on human macrophage heterogeneity." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238184.
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Wright, Adam. "The macrophage in cystic fibrosis." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/8783.
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Background: Cystic fibrosis (CF) is caused by absent/defective CF transmembrane conductance regulator protein (CFTR). CF is characterized by thick airway mucus, chronic infection and neutrophil inflammation leading to respiratory failure. I analysed airway macrophages (MΦs) and their expression of pattern recognition receptors (PRRs) in CF, since these cells are crucial to airway immune defence and they can orchestrate inflammation. I also performed transcript analysis of CF monocyte-derived MΦs (MDMs). Methods: Sputum was induced in CF paediatric and adult cohorts. Phenotype and function of CF MΦ were determined by flow cytometry and compared to controls. Monocytes (>92% purity) were grown in vitro to generate MDMs (n=15). Transcripts encoding the entire human genome were analysed (n=5) and expression of individual genes were confirmed by RT-PCR. Results: In classical CF (n=10) there was an increase in the proportion of monocyte-like small MΦs (of total MΦ) compared to controls (n=10) (73 ± 18% and 16 ± 8%, respectively, p< 0.0001). In non-classical CF (n=4), with milder lung disease, small MΦs increased to 31 ± 20% (p>0.05). PRRs were absent on small MΦs from CF and control. In contrast, clear expression could be detected on large MΦs from control but not CF. In line with this, CF small MΦs showed a strongly reduced uptake of particles compared to controls. Microarray analysis of MDMs revealed α- and β-tryptase as being significantly higher under constitutive and stimulated conditions in CF compared to control. However, using RT-PCR, expression of α- and β-tryptase was similar between groups. Conclusions: The phenotype of small MΦs in CF suggests that these cells are newly recruited monocytes from blood. Low expression of PRRs on these cells in CF and their reduced uptake indicates a reduced capacity to clear inhaled particles, which may contribute to further damage in CF. Further to this I was unable to confirm any transcript differences between CF and control MDMs due to mutant CFTR.
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Pound, J. D. "Parameters of human macrophage activation." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381442.
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Reid, Vanessa Claire. "Macrophage toxicity of lipid oxidation." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308384.
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Savill, John Stewart. "Macrophage recognition of senescent neutrophils." Thesis, Imperial College London, 1989. http://hdl.handle.net/10044/1/47641.
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Voelz, Kerstin. "Macrophage – cryptococcus interactions during cryptococcosis." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1194/.
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The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic effector cells. Cryptococcus can survive and proliferate within macrophages, and is also capable of escaping into the intracellular environment via a non-lytic mechanism (‘expulsion’) and can be transferred directly from one cell to another (lateral transfer). In the first part of this thesis, I demonstrate that enhanced Th2, but not Th1, cytokine levels lead to increased intracellular cryptococcal proliferation but lower levels of cryptococcal expulsion. In the second part, I describe the generation and characterisation of GFP-expressing derivates of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Furthermore, I have developed a method to effectively and rapidly investigate macrophage parasitism by flow cytometry that preserves the accuracy of current approaches but offers a four-fold improvement in speed. The final part dissects the regulation and induction of mitochondrial tubularisation in hypervirulent C. gattii strains and describes the first steps towards a comparative mitochondrial genome sequencing approach to identify the underlying molecular mechanisms.
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Hegyi, Laszlo. "Macrophage apoptosis and human atherosclerosis." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627017.
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Cano, Antonella. "Characterization of Acanthamoeba macrophage activation." Thesis, University of Strathclyde, 2015. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=25992.
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Goding, Linda M. "Macrophage Recognition of Xenogeneic Erythrocytes." University of Toledo Health Science Campus / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=mco1197469419.
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Erwig, Lars-Peter. "Macrophage programming in inflammatory disease." Thesis, University of Aberdeen, 2004. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU194083.
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Before embarking on the work presented here I showed that certain activating signals, such as IFN-gamma and TNF-alpha programmed macrophages to develop distinct sets of properties in vitro, which included unresponsiveness to other types of activation. This raised the question whether macrophage programming occurs in passive and active renal inflammation and whether the macrophage programme could be biased by systemic administration of cytokines. The data presented here shows that macrophages infiltrating acutely inflamed glomeruli of rats with nephrotoxic nephritis display programmed behaviour: operationally they behave as though programmed by IFN-gamma, and maintain these characteristics despite systematic administration of anti-inflammatory cytokines such as IL-4 or TGF-beta. This triggered further studies using a model of mesangioproliferative nephritis that can be adapted to induce resolving or progressive glomerular injury. These show that glomerular localisation does not always induce macrophage programming and that whether macrophages become programmed or not depends on the nature of the injury. Furthermore the data shows that macrophages become committed to a particular programme shortly after entering a programming environment. These observations raise question about the factors that induce macrophage programming at early stages of inflammatory disease and its consequences for its outcome. It provides an important mechanistic insight into how macrophage functional development is influenced by the underlying disease process.
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Hunter, Catriona Mhairi. "MicroRNA regulation of macrophage activation." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/31027.
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Macrophages are mononuclear phagocytic cells that have diverse roles within the body. Tissue specific macrophages, e.g. Kupffer cells, microglia and osteoclasts, have roles in tissue homeostasis, while circulating macrophages play an important role in the innate immune system. Macrophages detect the presence of pathogen associated molecular patterns (PAMPs) via a range of receptors known collectively as pathogen recognition receptors (PRRs). Detection of pathogens causes the macrophages to become ‘activated,’ during which the macrophages undergo extreme morphological and translational changes that enable the pathogen to be neutralised and other immune system components to be recruited. Macrophage activation must be carefully regulated and promptly resolved, as chronic inflammation is damaging to the host. MicroRNAs have emerged as one mechanism by which activation is regulated. MicroRNAs are small, non-coding pieces of RNA that function as a post-transcriptional regulatory mechanism. Their action is exerted through binding with a complementary region in the 3’ untranslated region (3’UTR) of the target mRNA. This binding, facilitated by the ribonuclear protein complex RISC, prevents successful translation of the mRNA into its protein product. MicroRNAs have been shown to function across species, throughout development and during the adult life-span. In the immune system, microRNAs are known to be required for correct formation of germinal centres and normal development of B- and T-cells. MicroRNAs have also been shown to be differentially regulated during macrophage activation with different stimuli. In particular, miR-155, miR-146a and miR-21 are associated with macrophage activation by lipopolysaccharide (LPS). The objective of this work was to further understand the role of microRNAs during macrophage activation with LPS. Two approaches were adopted. Firstly, the regulation of individual microRNAs in LPS-activated bone marrow derived macrophages (BMDMs) was characterised by the use of illumina small RNA sequencing. Secondly, the requirement of the global microRNA population during macrophage biology was investigated through the use of DGCR8 and Dicer knockout systems. In keeping with the large number of changes reported in mRNA translation upon activation, expression of >400 microRNAs were found to be differentially regulated by exposure to LPS. Twelve of these microRNAs were chosen for further study (miR- 142-3p, -146a, -15b, -155, -16, -191, -21, -27b, -30b, -322-5p, -378 and -7a). Individual knock-down of these microRNAs in the RAW264.7 macrophage-like cell line mostly demonstrated subtle, rather than dramatic changes to the activation marker genes studied by RT-QPCR analysis. However, knock-down of miR-146a, -15b, - 155 and -191 were able to significantly alter the expression of the activation marker genes (Tnf-a, Cox2, Cxcl2, Il-6 and Saa3). Interestingly, knock-down of miR-142-3p, miR-146a and miR-155 appeared to show cross-regulation of these microRNAs. The cell index (CI) data suggested that miR-191 and miR-21 influence adhesion in activated macrophages. Studies with the DGCR8 and Dicer knockout systems showed that the global microRNA population was required for successful differentiation of macrophages from embryonic stem cells, and for normal expression of differentiation and activation markers in bone marrow derived macrophages. Overall, these results show that dynamic expression of microRNAs is an integral part of the macrophage response to LPS.
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Holmes, Benjamin A. "The Construction of a Plasmid for Detecting the Pathway of Arginine Metabolism in Human Macrophages: a Real-Time Assessment of Macrophage Polarity." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1348874681.
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Shabo, Ivan. "Macrophage antigen expression in breast and colorectal cancers : A consequence of macrophage - tumour cell fusion?" Doctoral thesis, Linköpings universitet, Kirurgi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-54820.
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Carcinogenesis is a sophisticated biological process consisting of a series of progressive changes in somatic cells from premalignant to malignant phenotype. Despite the vast information available about cancer cells, the origin of cancer and cause of metastasis still remain enigmatic. The hypothesis of cell fusion is one of several models explaining the evolution of neoplasia into clinically significant cancer. This theory states that cancer cells through heterotypic fusion with host cells generate hybrids expressing traits from both parental cells, and acquire metastatic potentials and growth-promoting properties. The cell fusion theory is still unproven and speculative, but cell fusion is a common biological process in normal tissue. Accumulated evidence shows that macrophage-cancer cell fusion occurs in vitro and in vivo and produces hybrids with metastatic potential, but the clinical significant of cell fusion is unclear. The aim of this thesis is to test this hypothesis in clinical patient materials and to explore the clinical significance of macrophage phenotype traits in solid tumours. Paraffin-embedded cancer and normal tissue specimens from patients with breast cancer (n=133) and colorectal cancer (two different patient materials with totally 240 patients) were immunostained for the macrophage-specific antigen, CD163. The expression of CD163 was tested in relation to macrophage infiltration and tumour stage, survival time, irradiation, DNA ploidy, cancer cell proliferation and apoptosis. Phenotypic macrophage traits, such as the expression of CD163, were seen in both breast and colorectal cancers, and were correlated to advanced tumour stages and poor survival. CD163 expression was more frequent in rectal cancer after irradiation and was associated with decreased apoptosis. Cancer cell proliferation was correlated to both macrophage infiltration and CD163 expression. Multivariate analysis showed that CD163 is a significant prognostic factor in both breast and colorectal cancers. In an attempt to examine factors related to the function of macrophage fusion, the expression of the signalling adaptor protein DAP12 was tested and related to CD163 expression in breast cancers from 133 patients. DAP12 was shown to occur in breast cancer cells and was related to high histologic tumour grade, skeletal and liver metastasis, and poor prognosis. The findings in this thesis support the cell fusion theory and illustrate its clinical impact on tumour progression and metastasis.
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Park, Young Mi. "Interaction between CD36 and Oxidized LDL Modulates Macrophage Cytoskeletal Functions: A Mechanism of Macrophage Trapping." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270624670.
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Ellouze, Mehdi. "Identification des mécanismes anti-inflammatoires de GILZ dans les monocytes/macrophages et de son potentiel thérapeutique dans le choc septique." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS239/document.
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Le Sepsis et le choc septique, associés à une inflammation systémique sévère et incontrôlée, sont les principales causes de mortalité dans les unités de soins intensifs. Les macrophages jouent un rôle central dans ces pathologies. Ils participent à l'initiation et à la régulation de l'inflammation. Lors d'une infection bactérienne, ils reconnaissent le LPS de la paroi bactérienne par l’intermédiaire du TLR4 ce qui déclenche l’activation des MAPK, des facteurs de transcription NF-kB et AP1 et, in fine, la production des cytokines pro-inflammatoires dont le TNF et l'IL6. L’expression de la protéine GILZ dans les macrophages limite, in vitro, la production d'IL6 et de TNF en réponse au LPS. Cet effet est attribué à une inactivation de NF-kB. D’autre part, l'expression de GILZ décroît dans les macrophages humains et murins après une stimulation par du LPS.Compte tenu des effets régulateurs de GILZ dans les macrophages, les objectifs de notre étude sont 1) de déterminer si l’expression de GILZ est altérée dans les monocytes/macrophages (M/M) au cours du Sepsis, 2) de déterminer si une modulation de l’expression de GILZ dans les M/M est suffisante pour influencer l’inflammation systémique, et 3) d’identifier le mécanisme d'action de GILZ dans les M/M humains.Nous avons mesuré l’expression de GILZ dans les M/M de patients atteints de choc septique ou de syndrome de détresse respiratoire aiguë, et dans un modèle murin d’endotoxémie. Nous avons observé une diminution significative de GILZ dans ces contextes pathologiques chez l’homme et la souris. L'impact de cette altération a été exploré dans des souris transgéniques uniques dont les macrophages surexpriment GILZ de façon non régulable. Nous avons confirmé que la surexpression de GILZ limite la production de TNF et favorise celle de l'IL-10 dans les macrophages stimulés in vitro par du LPS. Nous avons ensuite étudié la réponse inflammatoire et la survie de ces souris dans un modèle d’endotoxémie et de choc septique, et montré que cette surexpression de GILZ restreinte aux macrophages limite la production sérique de cytokines pro-inflammatoires et, par conséquent, l'inflammation systémique en améliorant significativement la survie des souris. Ces résultats mettent en évidence les conséquences, au niveau systémique, de la régulation des macrophages par GILZ.Dans l’optique d’élucider les mécanismes impliqués dans la régulation des macrophages par GILZ, nous avons confirmé que GILZ inhibe NF-kB dans les macrophages humains sans toutefois retrouver l’interaction directe décrite entre GILZ murin et la sous-unité p65 de NF-kB.Ce résultat nous a conforté dans la nécessité de caractériser l’interactome de GILZ dans les macrophages humains. Deux approches complémentaires ont été utilisées. La première est un criblage pan-génomique des interactants de GILZ humain par la technique du double-hybride. La seconde méthode consiste en une purification d'affinité en tandem (TAP-TAG) de la protéine GILZ et de ses interactants, suivie d'une identification de ces protéines par spectrométrie de masse. Ce complexe a été isolé à partir d'extraits nucléaires ou cytoplasmiques de cellules humaines différenciées en macrophages et génétiquement modifiées afin d’exprimer la protéine GILZ flanquée des deux étiquettes nécessaires à sa purification. Ces deux approches ont mis en évidence des interactions nouvelles entre GILZ et des protéines clés de la signalisation du TLR4 dans les macrophages humains ainsi qu'un rôle probable de GILZ comme facteur régulateur de la transcription.Ces résultats montrent que la régulation de la réponse anti-inflammatoire des macrophages par GILZ a un impact sur l’inflammation systémique in vivo et améliore la survie dans un modèle de choc septique sévère. De plus, ces travaux identifient pour la première fois les partenaires cytoplasmiques et nucléaires de GILZ dans les macrophages humains et devraient permettre dans le futur, une meilleure compréhension de cette protéineSepsis and septic shock, associated with a severe and uncontrolled systemic inflammation, are the main causes of death in intensive care units. Macrophages play a central role in these pathologies. They are involved in the initiation and regulation of inflammation. They recognize LPS from the bacterial cell wall via TLR4, which triggers the activation of MAPK signaling pathway and transcription factors such as NF-KB and AP1 and ultimately, the production of pro-inflammatory cytokines including TNF and IL6. The expression of the protein GILZ in macrophages limits in vitro the production of IL6 and TNF in response to LPS. This effect is attributed to inactivation of NF-kB. Moreover, GILZ expression decreases in human and mouse macrophages exposed to LPS.Given the regulatory effects of GILZ in macrophages, the objectives of our study were 1) to determine whether GILZ expression is down-regulated in monocytes / macrophages (M/M) in the sepsis, 2) to determine whether the modulation of GILZ expression in M/M is sufficient to influence systemic inflammation, and 3) to identify GILZ mechanism of action in human M/M.GILZ expression was measured in the M/M of patients with septic shock or acute respiratory distress syndrome, and in a murine model of endotoxemia. We observed a significant reduced expression of GILZ in these pathological contexts in human and mice. The impact of this alteration was explored in unique transgenic mouse model in which macrophages stably overexpress GILZ (CD68-GILZ).We confirmed that GILZ overexpression limits TNF production and promotes IL-10 production in in vitro LPS-stimulated macrophages. We further studied the inflammatory response and survival of these mice in models of endotoxemia and septic shock. We showed that GILZ overexpression restricted to macrophages, limits serum pro-inflammatory cytokines production, therefore decreases systemic inflammation and significantly improves mice survival. These results highlight the effects of macrophage polarization by GILZ at a systemic level.This result confirmed the need to characterize GILZ interactome in human macrophages. Two complementary approaches have been used. The first one consists of a pan-genomic double hybrid screening of human GILZ partners. The second method consists of a tandem affinity purification (TAP-TAG) of GILZ protein and its associated partners, followed by the identification of these partners by mass spectrometry. Analyses have been performed independently on nuclear and cytoplasmic extracts from human macrophage cells, genetically engineered to express GILZ protein with the two tags required for purification. This dual approach led us to identify new direct and indirect interactions between GILZ and other key proteins of TLR4 signaling pathway in human macrophages and highlight a likely role of GILZ as a transcription regulatory factor.These results confirm the anti-inflammatory role of GILZ on systemic inflammation and enhancement of lifetime in murine models of endotoxemia and septic shock. Furthermore, this work identifies for the first time the cytoplasmic and nuclear GILZ partners in human macrophages and would allow in the future, a better understanding of GILZ mechanism of action
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Delfini, Marcello. "Jun regulates monocyte-derived macrophage accumulation and tumour progression." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0076.
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Les macrophages sont des cellules immunitaires innées présentes dans chaque organe. Ils sont des cibles thérapeutiques dans de nombreuses maladies, dont le cancer. En dépit de travaux récents sur l'origine des macrophages, les mécanismes régulant leur différenciation sont mal définis. L'expression de Jun, membre de la famille AP-1, augmente pendant la différenciation des macrophages, mais son rôle dans ce processus n'est pas connu.Au cours de mon doctorat, nous avons caractérisé le rôle de Jun dans le développement et l'homéostasie des macrophages, dans un modèle de souris avec délétion conditionnelle de Jun dans la lignée myéloïde (JunΔCsf1r). Nous montrons que Jun contrôle la différenciation, induite par CSF1, des monocytes en macrophages. In vivo, Jun régule l'accumulation de macrophages dérivés de monocytes dans les poumons et intestins. Les macrophages associés aux tumeurs (TAMs) jouent un rôle crucial dans la progression des cancers. L’absence de Jun freine la croissance d’un mélanome et la différenciation, induite par CSF1, des TAMs dérivés de monocytes qui participent à l’angiogénèse tumorale. Cependant, lors d'une inflammation aiguë, Jun n’affecte pas le recrutement de macrophages inflammatoires.En conclusion, nos résultats identifient Jun comme un régulateur central de la différenciation des macrophages. Dans un modèle de mélanome, les macrophages Jun-dépendants exercent des fonctions pro-tumorales. Le fait que Jun soit un régulateur sélectif du développement des macrophages dépendants de CSF-1 permettra de définir de nouvelles approches ciblant sélectivement la différenciation des macrophages, sans altérer les réponses immunitaires dépendantes des monocytesMacrophages are immune cells present in every organ. Given their variety of functions, macrophages are therapeutic targets in many diseases including cancer. Despite the research efforts to characterise their origins, the molecular mechanisms regulating macrophage differentiation are still poorly defined. Expression of the AP-1 factor, Jun, increases during differentiation, but its role in macrophage development is not known.During my PhD, we characterised how Jun affects macrophage development and homeostasis. We developed a conditional mouse model in which Jun is deficient in the myeloid lineage (JunΔCsf1r). We showed that Jun controls CSF1-mediated monocyte to macrophage differentiation, proliferation and survival. In vivo, Jun loss limits macrophage accumulation in lungs and intestine. Tumour-associated macrophages (TAMs) play critical roles in cancer progression. We observed that Jun deficiency dampens melanoma growth and the differentiation of CSF1-dependent monocyte-derived TAMs. We further showed that Jun-dependent TAMs mediate vessel normalisation in melanoma. During inflammation, Jun was dispensable for the recruitment of monocyte-derived inflammatory macrophages.Altogether, our results identify Jun as a master regulator of macrophage differentiation, without altering monocyte effector functions. In a melanoma model, we showed that Jun-dependent TAMs play tumour-promoting roles. Therefore, Jun is a selective regulator of CSF-1-dependent macrophage development, which is redundant during inflammation; this observation should help to define novel approaches to selectively target macrophage differentiation, without altering monocyte-dependent immune responses
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Chanez, Pascal. "Hétérogéneité morphologique et fonctionnelle des macrophages des voies aériennes de l'asthmatique." Montpellier 1, 1994. http://www.theses.fr/1994MON1T038.
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Rivier, Agnès. "Activation des phagocytes mononucléés chez les sujets normaux et les sujets asthmatiques/ Agnès Rivier." Montpellier 1, 1994. http://www.theses.fr/1994MON1T020.
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Haddad, Elias K. "Study of the role of macrophage activation and macrophage derived cytotoxic factors in early embryo loss." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ29928.pdf.
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Haddad, Elias K. "Study of the role of macrophage activation and macrophage derived cytoxic factors in early embryo loss." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42023.
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Using murine models of spontaneous and induced embryo resorption, we have investigated the role of macrophages in the mechanism of early embryo loss. The results showed that macrophage derived nitric oxide was associated with embryo resorption, and that decidual macrophages could be triggered by lipopolysaccharide (LPS) to produce nitric oxide, indicating that the decidual mononuclear cells were primed in situ. Using double immunostaining, we have shown that macrophages were the cellular source of the inducible nitric oxide production. We further showed that embryo abortion can be significantly decreased by inhibiting the production of nitric oxide in vivo. The results presented strongly suggested a role for nitric oxide as an effector molecule in mediating early embryo loss and showed that the in situ activation of decidual macrophages was an early event preceding spontaneous abortion.It is known that interferon-$ gamma$ (IFN-$ gamma$) is the major cytokine responsible for the priming of macrophages and that LPS can trigger primed macrophages to produce nitric oxide. Therefore, the observation that exogenous LPS induced embryo abortion in most strains of pregnant mice suggested that the decidual macrophages have been previously primed in situ. To investigate the role of IFN-$ gamma$ as a potential priming signal for decidual macrophage activation, we studied the effect of the depletion of IFN-$ gamma$ on LPS induced pregnancy loss. The results showed that IFN-$ gamma$ deficient mice were more resistant to LPS induced abortion than control mice. This suggested that IFN-$ gamma$ was essential for the priming of decidual macrophages and that decidual macrophages from IFN-$ gamma$ deficient mice could not be activated when exposed to LPS both in vivo and in vitro. Our results also showed increased IFN-$ gamma$ mRNA expression simultaneously in the same embryos that also expressed elevated iNOS mRNA, a macrophage activation marker. This suggested that macrophage activation, subsequent nitric oxide production, and spontaneous embryo loss could be a consequence of local IFN-$ gamma$ over production.
While LPS serves as an exogenous triggering factor, endogenous TNF-$ alpha$ is known to trigger NO production by primed macrophages. Therefore, we investigated the role of TNF-$ alpha$, as a second signal, in mediating embryo loss. Our studies showed that the frequency of embryos with significantly increased TNF-$ alpha$ mRNA expression corresponded to the incidence of murine embryo abortion. In addition, the results showed that increased TNF-$ alpha$ mRNA was simultaneously expressed with iNOS mRNA suggesting a potential role for TNF-$ alpha$ in the triggering of decidual macrophages.
In summary, we demonstrated the presence of activated decidual macrophages in murine placentas, and that inducible nitric oxide produced by these macrophages was responsible for embryo death. We further showed that IFN-$ gamma$ was responsible for the priming of decidual macrophages, and that the expression of TNF-$ alpha$, a potential secondary signal was associated with decidual macrophage activation, NO production, and subsequent embryo loss.
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Warby, Tammra. "Interactions between granulocyte-macrophage colony-stimulating factor and human monocyte-derived macrophages following infection with HIV-1 /." [St. Lucia, Qld.], 2006. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19318.pdf.
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Finney-Hayward, Tricia Kate. "Monocyte-derived macrophages as a lung macrophage model in chronic obstructive pulmonary disease : characterisation and functional output." Thesis, Imperial College London, 2005. http://hdl.handle.net/10044/1/8330.
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Walter, Michaela Roylene Valerie. "Macrophages in bovine footrot, the effect of Porphyromonas levii on macrophage function and pro-inflammatory cytokine production." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ65143.pdf.
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