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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

MACROPHAGE IRON CONTENT AND EXACERBATIONS OF COPD

Ho, Terence January 2019 (has links)
Background: Many COPD patients have recurrent exacerbations due to infection, but there are no valid predictors of this phenotype. Previously an observational study showed that higher iron content in sputum macrophages was associated with infectious exacerbations. Objectives: The thesis aimed to assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on bacterial uptake and killing, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. Methods: Intracellular iron was measured directly and indirectly in cell-line-derived and isolated sputum macrophages after treatment with exogenous IL-6, hepcidin or heat-inactivated H.influenzae. Bacterial uptake and killing were compared in both types of macrophages, in the presence or absence of iron-loading. A prospective cohort of COPD patients had their sputum hemosiderin index measured at baseline and were monitored for 1-year for infectious exacerbations requiring admission to hospital. Results: For pulmonary iron sequestration, IL-6 appears important, but the role of hepcidin is not clear. Iron-loading reduced the uptake of COPD-relevant organisms by almost one-third in cell-line-derived macrophage, and there was a near-significant linear relationship between sputum hemosiderin index and killing of H.influenzae (p=0.075). In terms of infective exacerbations, FEV1 had predictive utility (beta=-0.051, p=0.017) while a positive trend for sputum hemosiderin index (beta=0.035, p=0.051) suggests that this biomarker has clinical promise. Conclusion: Through in vitro experiments and cohort data, we have established a framework suggesting that excess iron in pulmonary macrophage may contribute to recurrent bacterial airway infection in COPD. IL-6 appears to contribute to sputum macrophage iron sequestration, which subsequently may lead to immune cell dysfunction and ultimately result in an increased frequency of infective exacerbation. / Thesis / Master of Science (MSc) / COPD patients often require hospitalization due to respiratory infections (bacterial or viral) that result in worsening of their breathing. It is difficult to predict who is at high risk for this to occur, which makes it harder to prevent. Many species of bacteria depend on iron as a nutrient. We wanted to see if iron being present in certain immune cells (macrophages) in the sputum could predict these flares by: testing how iron enters these cells, seeing if bacterial growth is altered by putting iron into these cells, and following a group of COPD patients and seeing if those with higher iron in their sputum had higher risk of infectious flares. Though more testing is needed, we found that a protein often present with chronic inflammation may be associated with higher sputum macrophage iron, and that there is evidence that killing of bacteria in COPD sputum macrophages is lower with high iron, and that patients with higher sputum iron are at greater risk of having infectious flares.
32

Les cellules Myéloïdes Dans le Microenvironnement Tumoral : Rôle de FasL / Myeloid cells in tumoral microenvironnement : Rôle of Fas ligand

Peyvandi, Sanam 09 July 2013 (has links)
La voie Fas-FasL est la voie majeure d’apoptose dont le rôle est indispensable pour l’homéostasie des cellules hématopoïétiques et la tolérance périphérique. Mon projet de thèse consiste à étudier le rôle de FasL dans la réponse anti tumorale, notamment le rôle de son expression sur les cellules myéloïdes, en l’occurrence les macrophages et les cellules myéloïdes suppressives.Les souris Fasl KO sont caractérisées par une accumulation des différentes populations de cellules hématopoïétiques dans les organes lymphoïdes périphériques. Cependant, elles ne développent pas de tumeurs spontanées. De façon intéressante, nos résultats montrent que lors qu’elles sont transplantées par les cellules tumorales, leur survie est significativement diminuée par rapport aux souris contrôles (Fasl fl/fl), ce qui suggère un rôle de FasL dans la réponse anti-tumorale. Une caractérisation fine de la répartition des cellules myéloïdes chez les souris Fasl KO porteuses de tumeur, montre une répartition différentielle des cellules Gr1+, par une accumulation des M-MDSC, dans la rate de ces souris. En plus, un enrichissement de l’infiltrat tumoral par les macrophages TAM chez les souris Fasl KO a été observé. Ces macrophages, indépendamment de génotype exècrent une forte activité d’arginase et iNOS et une inhibition de la prolifération des cellules T in vitro. Ainsi, la mortalité plus importante chez les souris Fasl KO pourrait, en partie, être associée à cet enrichissement des TAM dans l’infiltrat des souris déficientes en FasL.Afin de déterminer si cette accumulation des cellules myéloïdes immunosuppressives déficientes en FasL est spécifique d’un environnement tumoral ou le reflet d’un état inflammatoire, nous avons examiné le phénotype des macrophages dans un modèle d’inflammation induite par le thioglycollate. Les résultats montrent que les macrophages CD11b+F480+, recrutés sur le site de l’inflammation, lorsqu’elles sont déficientes en FasL, sur-expriment les gènes anti-inflammatoires comme IL-10, Arg1, CCL17. La caractérisation plus fine de cette population de macrophages a montré que la population responsable de ce phénotype suppressive est F480+CD115+IL-4R+. Chez les souris Fasl KO, le pourcentage des macrophages F480+CD115+IL-4R+ est significativement augmenté en comparaison avec les souris contrôles. L’analyse fonctionnelle de cette population CD115+ a montré que ces cellules, inhibent la prolifération et la production d’IFN- des cellules T activées. Ces caractéristiques fonctionnelles sont en faveur d’un phénotype anti-inflammatoire de ces macrophages, qui lorsqu’ils sont déficients en FasL, leur recrutement sur le site de l’inflammation est plus important.L’ensemble de ces résultats suggère que l’expression de FasL sur les cellules myéloïdes pourrait jouer un rôle dans leur polarisation vers un phénotype pro inflammatoire. Ainsi, ce travail pourrait apporter de nouvelles approches de levée de l’immunosuppression pour une immunothérapie efficace. / Fas-FasL pathway is the major pathway of apoptosis, the role of which is essential for the homeostasis of hematopoietic cells and peripheral tolerance. The project of my dissertation is to investigate the role of FasL in anti-tumor response, particulary the role of its expression on myeloid cells i.e., macrophages and myeloid derived suppressor cells. Fasl KO mice are characterized by an accumulation of different populations of hematopoietic cells in the peripheral lymphoid organs. However, they do not develop spontaneous tumors. Interestingly, our results show that when they are transplanted by tumor cells, their survival rate is significantly reduced in comparison to control mice, suggesting the implication of FasL in the anti-tumor response. Detailed characterization of the distribution of myeloid cells in Fasl KO mice injected with tumor cells shows a differential distribution of the sub populations of Gr1+ cells, an M-MDSC accumulation in the spleen. Furthermore, the enrichment of tumor infiltrate by suppressive macrophages in Fasl KO mice was observed. These macrophages, regardless of genotype, have a high arginase and iNOS activity and they inhibit the proliferation of T cells in vitro. Thus, the higher mortality in Fasl KO mice could in part be explained by the enrichment of tumor infiltrate by TAM in mice that are FasL deficient.To determine whether the accumulation of FasL deficient immunosuppressive myeloid cells is specific to a tumor environment or is the reflection of an inflammatory condition, we examined the phenotype of macrophages in an experimental inflammation induced by thioglycollate. The results show that CD11b + F480 + macrophages, which are recruited to the site of inflammation, when they are FasL deficient, they upregulate anti-inflammatory genes such as IL-10, Arg1, CCL17. More detailed characterization of this population of macrophages shows that the population responsible for the suppressor phenotype is F480+CD115+IL4R+. In Fasl KO mice, the percentage of F480+CD115+IL4R+ macrophages is significantly increased compared with control mice. Functional analysis of CD115+ population shows that they inhibit proliferation of activated T cells and their IFN-g production. These functional characteristics favor an anti-inflammatory phenotype of these macrophages, suggesting that when deficient in FasL, their recruitment to the site of inflammation is more important.Taken together, these results suggest that the expression of FasL on myeloid cells plays a significant role in their bias towards a pro inflammatory phenotype pointing toward a new class of approaches to raising immunosuppression for more effective immunotherapy.
33

Soluble negative regulators of goldfish primary kidney macrophage development

Nono, Berhanu Unknown Date
No description available.
34

Soluble negative regulators of goldfish primary kidney macrophage development

Nono, Berhanu 06 1900 (has links)
The generation of macrophages requires the coordinated responses to stimulatory and inhibitory signals that cell receive from their environment. While the up-regulation of macrophage production and survival is essential to fortify the immune system, their down-regulation is also vital to prevent macrophage related diseases and malignancy. Previous studies in goldfish showed that primary kidney macrophages release endogenous growth inducing factors into proliferative phase supernatant, which up-regulate their proliferation and survival. In this thesis, the effect of senescence phase supernatant (collected from goldfish primary kidney macrophage cultures) on goldfish primary kidney macrophages proliferation, survival and its impact on the ability of macrophages to tolerate H2O2 was analyzed. The results showed that the senescence phase supernatant down-regulated the proliferation and survival, and decreased the chemical tolerance of the cells. This indicated that the goldfish primary kidney macrophages promote targeted control of their proliferation and survival by secreting endogenous growth inhibitory factors in the senescence phase supernatant. / Physiology, Cell and Development Biology
35

Résolution de l'inflammation - infection dans les macrophages de patients atteints de mucoviscidose : impact de la membrane / Inflammation - infection in macrophages from patients with Cystic Fibrosis : membrane involvement

Lévêque, Manuella 14 December 2016 (has links)
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'inflammation. / Macrophages 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.
36

Nitric Oxide Production: A Mechanism of Chlamydia Trachomatis Inhibition in Interferon-γ-Treated RAW264.7 Cells

Chen, Bojun, Stout, Robert, Campbell, William F. 01 January 1996 (has links)
IFN-γ and/or LPS induced nitrite production and inhibition of Chlamynia trachomatis (CT) replication in the murine macrophage cell line, RAW264.7. Linear regression analysis demonstrated a strong correlation between nitrite production and inhibition of CT replication (correlation coefficients: -0.93, P < 0.001). L-NMMA specifically inhibited nitrite production and restored CT replication (55-71%). Inducible nitric oxide synthase (iNOS) mRNA was analyzed by Northern and dot blot hybridization with an iNOS cDNA probe. A strong correlation between iNOS mRNA expression and inhibition of CT replication also was observed (correlation coefficient: -0.97, P < 0.05). Furthermore, anti-TNF-α antibody, which completely neutralized biological activity of the secreted TNF-α neither inhibited nitrite production nor restored CT replication in the LPS- and/or IFN-γ-treated RAW264.7 cells. In mouse peritoneal macrophages treated with IFN-γ, both L-NMMA and anti-TNF-α antibody inhibited nitrite production and restored CT replication. However, L-NMMA and the antibody had no effect upon nitrite production and CT inhibition in LPS-treated peritoneal macrophages. These data indicate that NO production is one mechanism for inhibition of CT replication in IFN-γ-activated murine macrophages.
37

DIFFERENTIATION OF U-937 MONOCYTES TO MACROPHAGE-LIKE CELLS POLARIZED INTO M1 OR M2 PHENOTYPES ACCORDING TO THEIR SPECIFIC ENVIRONMENT: A STUDY OF MORPHOLOGY, CELL VIABILITY, AND CD MARKERS OF AN IN VITRO MODEL OF HUMAN MACROPHAGES

Abdulhadi, Fatma Husien S. 30 May 2014 (has links)
No description available.
38

The Construction of a Plasmid for Detecting the Pathway of Arginine Metabolism in Human Macrophages: a Real-Time Assessment of Macrophage Polarity

Holmes, Benjamin A. 01 October 2012 (has links)
No description available.
39

Myeloid AMPK in Atherosclerosis: Therapeutic Potential and Associated Mechanisms

LeBlond, Nicholas 13 October 2020 (has links)
Atherosclerosis propagates when innate immune cells, myeloid-derived macrophages, undergo unregulated uptake of cholesterol-rich modified low-density lipoproteins (LDL). Excess storage and retention of this cholesterol leads to development of lipid-laden macrophage foam cells, that accumulate within the intima of arteries as developing plaque. Formation of atherosclerotic lesions reduces blood flow and can further lead to more serious complications such as myocardial infarction, stroke, and cardiovascular disease. AMP-activated protein kinase (AMPK), a master regulator of cellular energetics, has been shown to participate in many anti-atherogenic pathways within myeloid cells such as (but not limited to) the inhibition of cholesterol synthesis and stimulation of reverse cholesterol transport. However, a recent report described a pro-atherogenic role for myeloid AMPK, showing it is expression required for myeloid cell recruitment and longevity within the atherosclerotic microenvironment. Despite this, multiple reports all corroborate describing a protective role for systemic pharmacological AMPK activation. We sought to determine the consequence of modified LDL variants in myeloid AMPK signaling and to further clarify the role of myeloid AMPK signaling within atherosclerosis. In cultured macrophages primed with modified LDL variants underwent AMPK activation, which was also associated with increased markers of autophagy. In an in vivo model of intermediate atherosclerosis, we observed that neither myeloid AMPK expression nor systemic AMPK-activating therapy influenced lesion myeloid content, necrosis, or autophagic markers. Furthermore, despite a suggestive trend, both myeloid AMPK and AMPK-therapy did not significantly influence lesion size in male or female mice. Interestingly, we found that in animals lacking AMPK signaling to only one substrate, HMGCR (the rate limiting enzyme in cholesterol synthesis), knock-in mice developed accelerated atherosclerosis when compared to their wild-type littermate. Furthermore, we determined that AMPK signaling to HMGCR in the hematopoietic compartment alone is enough to protect against atherogenesis. Taken together, these studies show the benefit of interrogating specific AMPK-regulated pathways in the context of atherosclerosis, and sheds light on the benefit of utilization of single point mutation knock-in models opposed to global or cell type-specific knockout models for investigations into AMPK within atherosclerosis.
40

Role of macrophage 11β-HSD1 in inflammation mediated angiogenesis, arthritis and obesity

Zhang, Zhenguang January 2014 (has links)
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by Hsd11b1) is an enzyme that predominantly converts inactive glucocorticoids (cortisone in human and most mammals, 11dehydro-corticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively). Thus 11β-HSD1 amplifies intracellular levels of glucocorticoids. Studies in globally 11β-HSD1 deficient mice have revealed changes in glucocorticoid-regulated physiological and pathological processes, including metabolism, aging, arthritis and angiogenesis. The function of macrophages, which play an important role in inflammation, is also altered. For example, 11β-HSD1 deficiency in macrophages causes a delay in their acquisition of phagocytic capacity. To dissect the role of macrophage 11β-HSD1 in angiogenesis, arthritis and obesity, both in vitro macrophage stimulation and in vivo functional assays in macrophage-specific 11β-HSD1 knockout mice, were conducted. Thioglycollate-elicited peritoneal macrophages from globally 11β-HSD1 deficient and control C57BL/6 mice were used for in vitro studies. In M1/M2 macrophage polarisation experiments, 11β-HSD1 deficient macrophages showed increased expression of mRNAs encoding pro-inflammatory factors upon lipopolysaccharide and interferon-ϒ treatment and decreased expression of pro-resolution genes with interleukin-4 stimulation. However, at cytokine or protein levels, there was little difference between the genotypes except for decrease IL12 p40 levels in 11β-HSD1 deficient macrophages. Hypoxic stress failed to show differences between genotypes in hypoxia-regulated gene expression. These data do not support a strong role for macrophage 11β-HSD1 in inflammation regulation, nor in response to hypoxia, at least when measured in vitro. The discrepancy between transcriptional and translational responses is currently unexplained, but may reflect altered posttranscriptional activity. To investigate the role of macrophage 11β-HSD1 in vivo, macrophage-specific Hsd11b1 knockout mice, LysM-Cre Hsd11b1 flox/flox (MKO) mice and Hsd11b1flox/flox littermate controls were generated. In MKO mice, 11β-HSD1 protein levels and enzyme activity were reduced by >80% in resident peritoneal macrophages. However, 11β-HSD1 protein and enzyme activity levels were unchanged or only modestly reduced in thioglycocollate-elicited peritoneal neutrophils, monocytes/macrophages, or in bone marrow-derived macrophages, despite >80% decrease in Hsd11b1 mRNA levels in these cells. A relatively long half-life of 11β-HSD1 protein compared to that of circulating myeloid cells may underlie this mismatch between transcriptional and translational expression. Furthermore, following 12 days of inflammatory arthritis induced by K/BxN serum transfer, the reduction in 11β-HSD1 protein levels in circulating neutrophils of MKO mice is consistently around 50%, which corroborates the above explanation. MKO mice and littermate controls were subjected to inflammatory models which may involve resident macrophages. First, to address the role of 11β-HSD1 in macrophages in angiogenesis, sponge implants were inserted subcutaneously into the flanks of adult male mice and harvested after 21 days. Chalkley counting on hematoxylin and eosin stained sponge sections showed significantly increased angiogenesis in MKO mice (scores: 5.2±1.0 versus 4.3±0.7; p<0.05, n=9-11). Cdh5 expression (encoding VE-cadherin, a marker of endothelial cells) was higher in sponges from MKO mice (relative expression: 1.5±0.9 versus 0.8±0.6; p<0.05), as was Il1b (encoding IL-1 beta, a marker of inflammation, relative expression: 6.5±6.4 versus 1.5±0.9; p<0.05). Vegfa mRNA (encoding vascular endothelial growth factor alpha) was unchanged, with a trend for higher Angpt1 (encoding angiopoietin 1, p=0.09) expression levels in the MKO group. These results suggest that lack of 11β- HSD1 in resident macrophages increases their pro-angiogenic activity, independently of VEGF-. The K/BxN serum transfer model of arthritis was used to investigate the role of macrophage 11β-HSD1 in arthritis. Adult male MKO and control mice received a single i.p. injection of 125μl K/BxN serum per mouse, followed by 21 days of clinical scoring to assess joint inflammation. The onset of inflammation (d1-8) was similar between MKO and control mice, but MKO mice exhibited greater clinical inflammation scores in the resolution phase of arthritis (d13-21; area-under-the-curve: 86.6±14.7 versus 60.1±13.4; p<0.005), indistinguishable from globally 11β-HSD1- deficient mice. Hematoxylin and eosin staining revealed pronounced fibroplasia predominantly in the supporting mesenchyme associated with the tenosynovium, with new bone and blood vessel formation. These results suggest that macrophage 11β-HSD1 deficiency is fully accountable for the worse arthritis resolution phenotype in the globally 11β-HSD1 deficient mice, but not the earlier onset of inflammation with global 11β-HSD1 deficiency. Macrophage activation states are closely linked with adipose insulin sensitivity. Globally 11β-HSD1 deficient mice are protected from high fat diet induced insulin resistance and adipose tissue hypoxia and fibrosis. To study the effect of macrophage 11β-HSD1 deficiency on insulin sensitivity, adult male MKO and control mice were given a 14 week high fat diet, which typically causes insulin resistance in control but not globally 11β-HSD1 KO mice. The level of fibrosis in subcutaneous adipose tissues was reduced as indicated by quantification of picrosirius red staining of collagen, though GTT data so far does not support protection from insulin resistance in MKO mice. In summary, in vitro macrophage polarisation experiments do not support a strong role of 11β-HSD in M1/M2 macrophage polarisations or response to hypoxia. However, MKO mice reveal, for the first time, an important in vivo role of macrophage 11β-HSD1 to promote angiogenesis and facilitate resolution of K/BxN serum transfer induced arthritis. Modulation of fibrosis is context dependent. Reduced adipose fibrosis may be one of the mechanisms that improve insulin sensitivity. Meanwhile, these findings suggest caution regarding the potential side effects of 11β-HSD1 inhibitors in treating metabolic disease in patients with inflammation-related co-morbidities, such as rheumatoid arthritis.

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