To see the other types of publications on this topic, follow the link: Modulation of macrophage activation.
Dissertations / Theses on the topic 'Modulation of macrophage activation'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Modulation of macrophage activation.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Wu, Wei-Kang. "Modulating angiogenesis via altering macrophage activation." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539772.
Full text
2
Olagnier, David. "Rôle des facteurs de transcription PPARgamma et Nrf2 dans la modulation de l'expression du récepteur scavenger CD36 des macrophages : implication dans la physiopathologie du paludisme." Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1308/.
Full textAbstract:
Le paludisme demeure la maladie parasitaire la plus meurtrière à travers le monde. La mise en place de nouvelles approches thérapeutiques dans la lutte contre ce pathogène semble indispensable. Les macrophages via le récepteur CD36 jouent un rôle crucial dans la reconnaissance et l'élimination des hématies infectées par P. Falciparum. Ainsi, le maintien d'un niveau élevé d'expression du récepteur CD36 à la surface des macrophages est un élément capital dans la lutte contre le parasite. L'établissement de l'infection est toujours associé à une production excessive de médiateurs pro-inflammatoires. Dans ce travail, nous montrons in vitro que les processus inflammatoires régulent négativement l'expression du récepteur CD36 à la surface des macrophages humains et murins et diminuent la clairance des hématies infectées. Dans ces conditions inflammatoires, nous démontrons que les ligands du récepteur nucléaire PPARgamma sont inefficaces pour promouvoir l'expression du récepteur CD36, phénomène directement associé à un défaut d'expression et d'activation de PPARgamma. Cependant, nous mettons en évidence pour la première fois que l'activation du facteur de transcription Nrf2 permet de restaurer indépendamment de PPARgamma l'expression et les fonctions antiplasmodiales du récepteur CD36. L'ensemble de ces résultats ont été reproduits in vivo dans un modèle de paludisme murin où seulement les activateurs de Nrf2 et non les ligands de PPARgamma contribuent à améliorer l'évolution de l'infection. Ces données soulignent le rôle important du facteur de transcription Nrf2 dans le traitement du paludisme via la modulation d'expression du récepteur CD36 des macrophages<br>Malaria remains the deadliest parasitic disease in the world. The introduction of new pharmacological approaches in the fight against this pathogen is essential. Macrophages through the expression of CD36 receptor play a crucial role in the recognition and the elimination of P. Falciparum infected erythrocytes. Therefore, maintaining an elevated level of CD36 receptor on the surface of macrophages is a crucial element in the struggle against the parasite. The establishment of malaria infection is always associated with an excessive production of pro-inflammatory mediators. In this work, we show in vitro that inflammatory processes negatively regulate the expression of CD36 receptor on the surface of human and mouse macrophages and hence decrease the clearance of parasitized erythrocytes. In these inflammatory conditions, we demonstrate that PPARgamma activators are ineffective to promote CD36 expression on macrophages, a phenomenon directly associated with a defect of both PPARgamma expression and activation. However, we highlight here for the first time that the activation of the Nrf2 transcription factor controls independently of PPARgamma the expression of CD36 receptor and its antiplasmodial function. All these results have been reproduced in vivo in a murine malaria model where only Nrf2 activators and not PPARgamma ligands contribute to improve the outcome of infection. Collectively, these data highlight the important role of the Nrf2 transcription factor in the control of malaria through the modulation of CD36 expression on macrophages
3
龔金斌 and Kam-pun Kung. "Modulation of plasminogen activator and plasminogen activator inhibitor system in murine macrophage." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1992. http://hub.hku.hk/bib/B31210351.
Full text
4
Chou, Ping-Jen. "The Modulation by Anthrax Toxins of Dendritic Cell Activation." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002791.
Full text
5
Lopardo-Spehner, Véronique. "Stress et immunomodulation : modulation de l'activation des macrophages murins apres stress experimental et role de l'immunomodulation therapeutique." Besançon, 1996. http://www.theses.fr/1996BESA3703.
Full text
6
Bergeron, Marc. "Modulations of mouse macrophage IFN-γ-dependent functions by the intracellular parasite Trypanosoma cruzi". Doctoral thesis, Université Laval, 2007. http://hdl.handle.net/20.500.11794/19087.
Full text
7
Endoh, Yasumi Medical Sciences Faculty of Medicine UNSW. "New mechanisms modulating S100A8 gene expression." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/42942.
Full textAbstract:
S100A8 is a highly-expressed calcium-binding protein in neutrophils and activated macrophages, and has proposed roles in myeloid cell differentiation and host defense. Functions of S100A8 are not fully understood, partly because of difficulties in generating S100A8 knockout mice. Attempts to silence S100A8 gene expression in activated macrophages and fibroblasts using RNA interference (RNAi) technology were unsuccessful. Despite establishing validated small interfering RNA (siRNA) systems, enzymaticallysynthesized siRNA targeted to S100A8 suppressed mRNA levels by only 40% in fibroblasts activated with FGF-2+heparin, whereas chemically-synthesized siRNAs suppressed S100A8 driven by an S100A8-expression vector by ~75% in fibroblasts. Suppression of the gene in activated macrophages/fibroblasts was low, and some enzymatically-synthesized siRNAs to S100A8, and unrelated siRNA to GAPDH, induced/enhanced S100A8 expression in macrophages. This indicated that S100A8 may be upregulated by type-1 interferon (IFN). IFN-β enhanced expression, but did not directly induce S100A8. Poly (I:C), a synthetic dsRNA, directly induced S100A8 through IL-10 and IFN-dependent pathways. Induction by dsRNA was dependent on RNA-dependent protein kinase (PKR), but not cyclooxygenase-2, suggesting divergent pathways in LPS- and dsRNA-induced responses. New mechanisms of S100A8 gene regulation are presented, that suggest functions in anti-viral defense. S100A8 expression was confirmed in lungs from influenza virus-infected mice and from a patient with severe acute respiratory syndrome (SARS). Multiple pathways via mitochondria mediated S100A8 induction in LPS-activated macrophages; Generation of reactive oxygen species via the mitochondrial electron transport chain and de novo synthesis of ATP may be involved. This pathway also regulated IL-10 production, possibly via PKR. Extracellular ATP and its metabolites enhanced S100A8 induction. Results support involvement of cell stress, such as transfection, in S100A8 expression. A breast tumor cell line (MCF-7) in which the S100A8 gene was silenced, was established using micro RNA technology; S100A8 induction by oncostatin M was reduced by >90% in stably-transfected cells. This did not alter MCF-7 growth. The new approach to investigate the role of S100A8 in a human tumor cell line may assist in exploring its functions and lead to new studies concerning its role in cancer.
8
Raposo, Rui Andre Saraiva. "T cell activation-induced soluble factors trigger CD4 down-modulation in human macrophages : Consequences for HIV-1 infection." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533875.
Full text
9
Galuppo, Mariana Kolos. "Análise da atividade de CD100 na modulação da ativação de macrófagos e sua infectividade por Leishmania (Leishmania) amazonensis." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-21092012-085336/.
Full textAbstract:
Considerando a importância do perfil do macrófago na infecção por Leishmania e o potencial papel de CD100 na modulação da ativação do m<font face=\"Symbol\">j, postulamos que essa molécula pode afetar a infectividade dessa célula por este parasita. Portanto, analisou-se e comparou-se a expressão de CD100 em diferentes tipos de m<font face=\"Symbol\">j (BALB/c e C57BL/6) e seus efeitos em termos de ativação e infecção com L. amazonensis. Avaliamos a expressão de CD100 e observamos que m<font face=\"Symbol\">js peritoneais de BALB/c expressam mais CD100 do que os de C57BL/6 e que esta expressão diminui ao longo da infecção. M<font face=\"Symbol\">j de BALB/c pré-tratados com sCD100 antes da infecção tem maior índice no tempo de 4h e quando em contato com o sCD100 antes, durante e após a infecção, o índice aumenta em 4 e 24h. Em m<font face=\"Symbol\">j de C57BL/6 pré-tratados com sCD100 ou no período de infecção, o índice aumenta em 4h. Quando permanecem durante todo o tempo em contato com o sCD100 o índice aumenta nos períodos de 4 e 24h. Concluímos que o CD100 pode estar relacionado com a modulação da infecção, e que a infecção afeta a expressão dessa molécula pelo m<font face=\"Symbol\">j.<br>Considering the importance of m<font face=\"Symbol\">j in Leishmania´s infection and the potential role of CD100 in the modulation of m<font face=\"Symbol\">j activation, we postulated that this molecule may affect m<font face=\"Symbol\">j infectivity. Therefore, we analyzed and compared the expression of CD100 on different types of m<font face=\"Symbol\">j (BALB/c and C57BL/6) and their effects in terms of m<font face=\"Symbol\">j activation and infectivity by L. amazonensis. We analyzed the expression of CD100 and the results suggest that m<font face=\"Symbol\">j from BALB/c express more CD100 than C57BL/6 and this expression decrease along the infection. M<font face=\"Symbol\">j from BALB/c pre-treated with sCD100 have augmented infection rates in 4h and in contact with the sCD100 before, during and after infection, increase rates in periods of 4 and 24h. In m<font face=\"Symbol\">j from C57BL/6 pre-treated with sCD100 or infection period, the rates increase in 4h. When macrophages remained in contact with sCD100 throughout the infection, rates increase after 4 and 24h. We can therefore conclude that CD100 may be related to modulation of Leishmania´s infection and that the infection itself affects CD100 expression in m<font face=\"Symbol\">j.
10
Prat, Mélissa. "Les macrophages au sein du microenvironnement tumoral : étude et modulation des mécanismes moléculaires et cellulaires de la réponse anti-tumorale au cours de carcinoses péritonéales." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30116.
Full textAbstract:
Les macrophages (Mφs) possèdent une remarquable plasticité phénotypique et fonctionnelle qui leur permet de s’adapter aux différents signaux de leur microenvironnement. Au sein du microenvironnement tumoral, les Mφs ou TAMs (Tumor-associated Mφs) représentent la population leucocytaire majeure. Au cours du développement tumoral, les cellules transformées contribuent à éduquer les TAMs qui acquièrent alors des propriétés permissives à la croissance tumorale. Ainsi, il est aujourd’hui admis que les TAMs, initialement de phénotype M1 anti-tumoral, vont se différencier vers un phénotype M2 capable de favoriser la prolifération des cellules tumorales, l’angiogenèse, les métastases, la résistance aux traitements de chimiothérapie et la suppression de la réponse immunitaire adaptative anti-tumorale. Cependant, cette dichotomie fonctionnelle M1/M2, bien que facilitant la description du phénotype des TAMs et de leurs fonctions, est une simplification de la biologie des Mφs au sein du tissu cancéreux qui est en réalité plus complexe. Ainsi, dans la première partie de ce travail de thèse, nous avons montré que l’IL-13, une cytokine Th2 bien décrite pour être impliquée dans la polarisation M2 des Mφs, inhibe la croissance tumorale d’un lymphome T et d’un adénocarcinome ovarien via la promotion de l’activité cytotoxique des Mφs. De manière intéressante, nous avons mis en évidence le rôle clé des récepteurs Lectine de type C Mannose (RM) et Dectine-1, fortement exprimés à la surface des Mφs polarisés par l’IL-13, dans la reconnaissance des cellules tumorales. Nous avons identifié l’acide sialique exprimé à la surface des cellules transformées comme un épitope critique à leur reconnaissance par les Mφs polarisés par l’IL-13. De plus, nous avons montré que, suite à cette reconnaissance, RM et Dectine-1 sont impliqués dans le déclenchement de voies de signalisations cytotoxiques menant à la production de radicaux libres oxygénés et d’arginase, deux médiateurs responsables de l’élimination des cellules tumorales par nécrose. Dans la seconde partie de ce travail, nous avons étudié l’impact du 15(S)-HETE, un ligand naturel du récepteur nucléaire PPAR-γ impliqué dans la polarisation M2 des Mφs, sur le développement tumoral. Nous avons montré que ce lipide inhibe la croissance tumorale dans un modèle murin d’adénocarcinome ovarien. De façon intéressante, nous avons démontré que cet effet anti-tumoral est dépendant de l’activation de PPAR-γ dans les Mφs. Nous avons mis en évidence que le 15(S)-HETE modifie la balance des populations de Mφs présentes au niveau de la cavité péritonéale, probablement en induisant la différenciation des Small Peritoneal Mφs (SPM) en Large Peritoneal Mφs (LPM). Ces derniers possèdent un phénotype qui contribue à augmenter le ratio lymphocytes T effecteurs/régulateurs au niveau de l’ascite tumorale, et ainsi à contrecarrer l’immunosuppression induite par la tumeur. Enfin, dans la troisième partie de ce travail nous mettons en évidence une forte hausse de la population de monocytes intermédiaires (CD14high CD16high) dans le sang d’une cohorte de 19 patientes atteintes de cancer ovarien séreux de haut grade. De manière intéressante, nous avons démontré qu’il existe une corrélation positive entre la présence de cette population intermédiaire au niveau du sang et la présence d’un microenvironnement immunosuppresseur au niveau de l’ascite de ces patientes (↗ Tregs, ↗ TAMS CD163high CD206high CCR2high CD86low et ↘ NK et CD8+ cytotoxiques). De plus, nous avons mis en évidence une corrélation positive entre l’expansion de ces monocytes intermédiaires et le développement tumoral au sein du péritoine. Ensemble, ces données souligne le rôle des monocytes sanguins comme signature prédictive du statut immun et du développement tumoral au sein du péritoine chez des patientes atteintes de cancer ovarien<br>Macrophages, which are crucial effectors of innate immune response, exhibit a remarkable phenotypic and functional plasticity that allows them to adapt to the different stimuli present in their microenvironment. Within the tumor microenvironment, macrophages or TAMs (Tumor-associated macrophages) represent the major leukocyte population. During tumor development, secreted mediators produced by transformed cells « educate » TAMs which acquire properties favorable to tumor growth. Thus, it is now widely accepted that TAMs, initially of anti-tumor M1 phenotype, differentiate towards an M2 phenotype able to promote tumor cell proliferation, angiogenesis, metastases, resistance to chemotherapy treatments and suppression of the adaptive anti-tumor immune response. However, this functional M1/M2 dichotomy, while facilitating the description TAMs phenotype and their associated functions, is an oversimplification of the macrophage biology within tumor tissues which is actually more complex. Thus, in the first part of this work, we showed that treatment with IL-13, a Th2 cytokine well described to be involved in macrophage M2 polarization, inhibits tumor growth in two murine models of T-cell lymphoma and ovarian adenocarcinoma via the promotion of macrophage cytotoxic activity. Interestingly, we demonstrated the key role of Mannose (RM) and Dectin-1 C-type Lectin receptors, strongly expressed on IL-13-activated macrophages, in tumor cell recognition. We specifically identified the sialic acid expressed on transformed cell surface as a critical epitope for their recognition by IL-13-activated macrophages. Moreover, we showed that, following this recognition, RM and Dectin-1 trigger cytotoxic signaling pathways leading to the production of radical oxygen species and the amplification of arginase activity. We finally demonstrated that these two mediators produced by IL-13-activated macrophages induce tumor cell necrosis. In the second part of this work, we studied the impact of 15(S)-HETE, a natural ligand of the PPAR-γ nuclear receptor involved macrophage M2 polarization, on tumor development. We showed that this lipid inhibits tumor growth in an experimental murine model of ovarian adenocarcinoma. Interestingly, we demonstrated that 15(S)-HETE anti-tumor effect depends on the activation of PPAR-γ in macrophages. We showed that 15(S)-HETE modifies peritoneal macrophage population balance, likely by promoting the differentiation of Small Peritoneal Macrophages (SPM) into Large Peritoneal Macrophages (LPMs). These LPMs display a phenotype which contributes to the increase of effector/regulatory T lymphocyte ratio in tumor ascites, and thus counteracts tumor-induced immunosuppression. Finally, in the third part of our work, the analysis of circulating blood monocytes in ovarian adenocarcinoma patients revealed a strong increase in the proportion of the « intermediate » subset (CD14high CD16+), usually poorly represented in healthy subjects. Interestingly, we demonstrated a positive correlation between a high proportion of intermediate blood monocytes and the presence of an immunosuppressive microenvironment in the tumor ascites of these patients (↗ Tregs, TAMS CD163high CD206high CCR2high CD86low and ↘ NK and CD8 + cytotoxic). In addition, we showed a positive correlation between the expansion of these intermediate monocytes and tumor development within the peritoneum. Together, these data highlight the role of blood monocytes as a predictive signature of immune status and tumor development within the peritoneum in patients with ovarian cancer
11
Drajac, Carole. "Caractérisation et modulation de la réponse immunitaire innée au cours de l’infection par le Virus Respiratoire Syncytial en période néonatale." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLA014/document.
Full textAbstract:
Le Virus Respiratoire Syncytial (VRS) est responsable de 70 % des cas de bronchiolite chez les enfants de moins de cinq ans. La survenue de bronchiolites sévères chez le nourrisson est un facteur de risque de développement d’asthme en grandissant. Aucun vaccin contre le VRS n’est disponible chez l’Homme. Le système immunitaire inné est la première ligne de défense de l’organisme contre les infections. De plus, en interaction avec la flore bactérienne commensale des poumons, l’immunité innée participe à la maturation de la réponse immunitaire adaptative qui confère à l’individu une protection sur le long terme vis-à-vis des pathogènes. Afin d’expliquer la susceptibilité néonatale au VRS, nous avons caractérisé un nouveau mécanisme de contrôle de la réponse innée antivirale lors de l’infection de souriceaux. Nous avons également testé une nouvelle approche de modulation de la réponse immunitaire au VRS par le microbiote pulmonaire. Ainsi, mieux comprendre les mécanismes immunologiques et virologiques responsables de bronchiolites sévères en période néonatale permettra de développer des moyens de lutte sûrs et efficaces contre l’infection par le VRS<br>Respiratory Syncytial Virus (RSV) is responsible for 70 % of bronchiolitis in children under five years old. Severe bronchiolitis in infants is a risk factor for asthma development. No vaccine against RSV is available in humans. The innate immune system is the first line of defense against infections. Moreover, in interaction with lung microbiota, innate immunity shapes adaptive immune response responsible for long-term protection against pathogens. To explain the susceptibility of young children to RSV, we characterized a novel regulatory mechanism of the innate antiviral response during neonatal RSV infection in the murine model. We also tested a new approach for modulating immune responses to RSV by the pulmonary microbiota. Thus, a better understanding of immunological and virological mechanisms responsible for severe bronchiolitis during the neonatal period will allow the development of safe and effective therapeutic strategies against RSV infection
12
Pound, J. D. "Parameters of human macrophage activation." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381442.
Full text
13
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.
Full text
14
Hunter, Catriona Mhairi. "MicroRNA regulation of macrophage activation." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/31027.
Full textAbstract:
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.
15
Heasman, Sarah Jane. "Glucocorticoid modulation of macrophage function." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29146.
Full textAbstract:
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.
16
Ghanipour, Ali. "IL-10 regulates macrophage activation through activation of SHIP." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30873.
Full textAbstract:
IL-10 is a potent anti-inflammatory and immunosuppressive cytokine, which
regulates macrophages by activation of the STAT3 pathway. However, several lines of
evidence suggest that IL-10 can inhibit macrophage activation independent of STAT3
through currently unknown mechanisms and pathways. Here for the first time, we show
that in murine macrophages, IL-10 activates Src Homology 2 Domain-containing Inositol
5'-Phosphatase (SHIP), a molecule with reported anti-inflammatory effects. Activation
of SHIP by IL-10 is required for inhibition of Tumor necrosis factor alpha (TNFα) in
macrophages. Additional experiments revealed that IL-10 activation of SHIP acted at the
post-transcriptional level and inhibited translation of TNFα . Using a novel small
molecule activator of SHIP, AQX-016A, we further confirmed that activation of SHIP
alone could inhibit TNFα translation.
IL-10 activation of SHIP results in the inhibition of the LPS induced increase in
the PI3K product, PIP3, at the membrane. However, conflicting data as to the role of
PI3K in regulation of TNFα have been presented. Our studies show that PI3K inhibition
downregulates TNFα production in peritoneal and several other macrophage lines, and
upregulates it bone marrow derived macrophages (BMDM). Interestingly, this difference
is due to the increased amount of autocrine negative regulators produced in BMDM,
removal of which exposes the positive role PI3K plays in regulation of TNFα. Therefore,
our studies confirm that PI3K activity positively regulates TNFα production in
macrophages and that inhibition of TNFα by IL-10 or AQX-016A through activation of
SHIP is likely due to SHIP'S ability to antagonize this pathway. The importance of this pathway is further highlighted as IL-10 inhibition of LPS-induced septic shock in mice
lacking one allele of SHIP is significantly attenuated. Furthermore, activation of SHIP
by AQX-016A inhibits TNFα production in septic mice.
We also found that IL-10 inhibited LPS induced p38 activity in a cell-dependent
manner. However in all cells tested, IL-10 activated p38 rapidly. We identified several
IL-10 induced genes including CRIM1, a transmembrane protein with no previous report
of involvement in the immune system. We found that IL-10 induction of CRIM1 was
partly dependent on the activity of p38. However, expression of CRIM1 does not seem
to be involved in the anti-inflammatory effects of IL-10.<br>Medicine, Faculty of<br>Biochemistry and Molecular Biology, Department of<br>Graduate
17
DUARTE, Madalena Bento. "Macrophage direct activation by Leishmania Spp." Master's thesis, Instituto de Higiene e Medicina Tropical, 2019. http://hdl.handle.net/10362/97877.
Full textAbstract:
Leishmanioses é um grupo de doenças causadas por parasitas do género Leishmania que apresenta elevada morbidade e de mortalidade. As manifestações clínicas dependem de interações complexas que se estabelecem entre Leishmania spp. e a resposta imunitária do hospedeiro. A doença pode manifestrar-se de maneiras diferentes, desde uma simples úlcera cutânea até ao envolvimento dos órgãos profundos que pode originar doença visceral fatal ou kala-azar. A resistência a drogas terapêuticas é um problema muito evidente em países endémicos, existindo uma crescente procura por alternativas eficazes. A pesquisa de vacina(s) capaz de deter a propagação da doença tem sido exaustiva. Um dos aspectos mais importante de Leishmania spp. é a capacidade destes parasitas conseguirem, por um lado, evitar e, por outro, alterar a resposta imunitária do hospedeito, que permita a sobrevivência do parasita e do hospedeiro, originando infeção crónica. O objectivo desta dissertação é investigar a capacidade de Leishmania spp. (L.shawi, L.amazonensis, L.guyanensis e L.infantum) modular a activação de MØ humanos, avaliando o fenótipo de MØ infetados através da expressão de dois biomarcadores de superfície, o CD68 e o CD163, associados à fagocitose e á actividade oxidativa. Os resultados mostraram que promastigotas de Leishmania induziram a mudança no fenótipo dos MØ que aponta para a existência de fagocitose intensa e inibação da actividade oxidativa. O incremento da fagocitose associado á diminuição da actividade oxidativa dos MØ infetados facilita o estabelecimento da infeção no hospedeito humano, garante a sobrevivência do parasita e assegura a conclusão do seu ciclo de vida, sobretudo nos parasitas causadores de leishmaniose cutânea<br>Leishmanias is a group of diseases with different clinical manifestations and is the leading cause of high morbidity and mortality worldwide. The clinical manifestations of Leishmanias in humans depend on complex interactions between the virulence characteristics of infecting Leishmania spp. and the immune responses of its hosts. The disease can manifest in a number of forms, ranging from simple cutaneous ulcers to the involvement of visceral organs, causing highly fatal visceral disease or kala-azar. Drug resistance is a very evident problem in some of endemic countries within the increasing demand for effective alternatives. The urgent demand for a vaccine capable of halting the spread of the disease has been exhausting. One of the most important aspects of Leishmania spp. infection is the ability of these parasites to evade and sabotage the host immune responses, which allow the parasite to persist and established chronic infection. The aim of the present dissertation is to investigate Leishmania spp. (L. shawi, L. amazonensis, L. guyanensis, and L. infantum) ability in modulating MØ activation, by accessing cell phenotype through the expression of two surface biomarkers, CD68 and CD163that are associated with phagocytosis and oxidative burst. Results showed that Leishmania promastigotes induced a change in MØ phenotype that point towards active phagocytosis and inhibition of the oxidative burst. Modulating the MØ activity to increase phagocytosis and decrease oxidative burst allows the parasite to establish host infection and ensures their own survival and the accomplishment of the life cycle, at least by the parasites that cause cutaneous leishmaniasis.
18
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.
Full text
19
Castro, Mike. "Cytokine Modulation of Cardiomyocyte-Macrophage Interaction." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright157858331333014.
Full text
20
Burrowes, Hannah Mahony. "Macrophage Activation and Differentiation with Cholesterol Crystals." Thesis, University of Canterbury. Biological Sciences, 2012. http://hdl.handle.net/10092/7532.
Full textAbstract:
Cholesterol crystals have been linked to activation of the NLRP3
inflammasome and the formation of foreign body giant cells (FBGCs). It
has been hypothesized that FBGCs have a role in advanced atherosclerotic
plaque formation. This thesis examined the feasibility of producing
stable cultures of FBGCs starting with human monocytes with the
goal to examine pterin production by these cells in comparison to
human monocyte derived macrophages (HMDMs). The study also
investigated the effect of cholesterol crystals on 7,8-dihydroneopterin
(7,8-NP) production and modulation of IL-1β levels in macrophages.
7,8-Dihydroneopterin is a potent antioxidant generated by macrophages
which also down regulates the expression of macrophage scavenger
receptor CD36. The use of alpha-tocopherol and IL-4 as FBGC fusion
mediators was explored. Using these mediators, large numbers of
FBGC were successfully cultured. The rates of fusion achieved in the
cultures were low, and the cells had poor adhesion, which prevented
pterin measurement. FBGC, which are thought to remove crystallized
cholesterol from the plaque, cleared 21% of cholesterol crystal compared
to 50% cleared by HMDM cells. Due to this result, the effect of
cholesterol crystals on pterin production in monocytes and macrophages
was explored. Cholesterol crystals cause inflammation through the
activation of the NLRP3 inflammasome, however, it was unknown
whether they could modulate 7,8-NP production. Cholesterol crystals
caused an intracellular dose-dependent loss of 7,8-NP to its oxidized form,
neopterin, in HMDM cells. Cholesterol crystals induced intracellular
synthesis of 7,8-NP in HMDMs. 7,8-NP was released into the supernatant
and oxidized to neopterin in media. Monocytes treated with cholesterol
crystals released up to 100 nM of neopterin and 120 nM of 7,8-NP in
the media after 48 hours. The combination of IFN- and cholesterol
crystals appeared to inhibit the release of 7,8-NP into the media for the
first 48 hours, after this time 7,8-NP release rapidly increased. The
addition of exogenous 200 μM 7,8-NP showed that in the presence of
monocytes, cholesterol crystals did not cause the oxidation of 7,8-NP to
neopterin, as seen in HMDMs but possibly to 7,8-dihydroxanthopterin
or xanthopterin. The presence of 7,8-NP increased IL-1β expression in
the presence of cholesterol crystals after 24 hours incubation. FBGCs
and the removal of cholesterol crystals may be a key process in the
resolution of atherosclerotic plaques. It appears that cholesterol crystals
are able to modulate inflammatory processes including activation of
the inflammasome and balance of 7,8-dihydroneopterin to the oxidized
neopterin. The infiltrating monocytes may provide antioxidant protection
against the inflammation induced by cholesterol crystals and the activity
of the infammasome.
21
Hamerman, Jessica Ann. "Macrophage activation during Mycobacterium bovis BCG infection /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8359.
Full text
22
Steck, Ryan Perry. "Pharmacologic Immunomodulation of Macrophage Activation by Caffeine." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4251.
Full textAbstract:
Caffeine is one of the most widely used neurostimulants in the world and there is considerable debate on its effect in immune cells. One of its main targets is proposed to be adenosine receptors which mediate an anti-inflammatory switch in activated immune cells while another target is phosphodiesterase where it acts as an inhibitor. In macrophages, caffeine has been shown to cause both pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. If the primary effect of caffeine on macrophages were to antagonize adenosine receptors we would expect cells exposed to caffeine to have a prolonged M1 response. However, we show that caffeine suppresses phagocytosis at physiological concentrations (an indicator of M2 phenotype). This suppression was reversed when macrophages were pretreated with protein kinase A inhibitor, suggesting that at physiological concentrations caffeine's phagocytic suppression may be due to its function as a phosphodiesterase inhibitor, pushing cells towards an M2 fate. However, mRNA expression profiling suggests that caffeine can modulate A2A receptor expression and suppress MKP-1 expression, a hallmark of M1 macrophages. Caffeine is, therefore an immunomodulator that can suppress or prolong inflammatory responses in macrophages, which may account for the abundance of contradicting evidence in the literature. Additionally, these effects are complicated by regular caffeine intake and fitness level, emphasizing that tolerance and immune robustness are important factors in macrophage activation.
23
Raza, Sobia. "Modelling and analysis of macrophage activation pathways." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5898.
Full textAbstract:
Macrophages are present in virtually all tissues and account for approximately 10% of all body mass. Although classically credited as the scavenger cells of innate immune system, ridding a host of pathogenic material and cellular debris though their phagocytic function, macrophages also play a crucial role in embryogenesis, homeostasis, and inflammation. De-regulation of macrophage function is therefore implicated in the progression of many disease states including cancer, arthritis, and atherosclerosis to name just a few. The diverse range of activities of this cell can be attributed to its exceptional phenotypic plasticity i.e. it is capable of adapting its physiology depending on its environment; for instance in response to different types of pathogens, or specific cocktail of cytokines detected. This plasticity is exemplified by the macrophages capacity to adjust rapidly its transcriptional profile in response to a given stimulus. This includes interferons which are a group of cytokines capable of activating the macrophage by interacting with their cognate receptors on the cell. The different classes of interferons activate downstream signalling cascades, eventually leading to the expression (as well as repression) of hundreds of genes. To begin to fully understand the properties of a dynamic cell such as the macrophage arguably requires a holistic appreciation of its constituents and their interactions. Systems biology investigations aim to escape from a gene-centric view of biological systems. As such this necessitates the development of better ways to order, display, mine and analyse biological information, from our knowledge of protein interactions and the systems they form, to the output of high throughput technologies. The primary objectives of this research were to further characterise the signalling mechanisms driving macrophages activation, especially in response to type-I and type- II interferons, as well as lipopolysaccharide (LPS), using a ‘systems-level’ approach to data analysis and modelling. In order to achieve this end I have explored and developed methods for the executing a ‘systems-level’ analysis. Specifically the questions addressed included: (a) How does one begin to formalise and model the existing knowledge of signalling pathways in the macrophage? (b) What are the similarities and differences between the macrophage response to different types of interferon (namely interferon-β (IFN-β) and interferon-γ (IFN-γ))? (c) How is the macrophage transcriptome affected by siRNA targeting of key regulators of the interferon pathway? (d) To what extent does a model of macrophage signalling aid interpretation of the data generated from functional genomics screens? There is general agreement amongst biologists about the need for high-quality pathway diagrams and a method to formalize the way biological pathways are depicted. In an effort to better understand the molecular networks that underpin macrophage activation an in-silico model or ‘map’ of relevant pathways was constructed by extracting information from published literature describing the interactions of individual constituents of this cell and the processes they modulate (Chapter-2). During its construction process many challenges of converting pathway knowledge into computationally-tractable yet ‘understandable’ diagrams, were to be addressed. The final model comprised 2,170 components connected by 2,553 edges, and is to date the most comprehensive formalised model of macrophage signalling. Nevertheless this still represents just a modest body of knowledge on the cell. Related to the pathway modelling efforts was the need for standardising the graphical depiction of biology in order to achieve these ends. The methods for implementing this and agreeing a ‘standard’ has been the subject of some debate. Described herein (in Chapter-3) is the development of one graphical notation system for biology the modified Edinburgh Pathway Notation (mEPN). By constructing the model of macrophage signalling it has been possible to test and extensively refine the original notation into an intuitive, yet flexible scheme capable of describing a range of biological concepts. The hope is that the mEPN development work will contribute to the on-going community effort to develop and agree a standard for depicting pathways and the published version will provide a coherent guide to those planning to construct pathway diagrams of their biological systems of interest. With a desire to better understand the transcriptional response of primary mouse macrophages to interferon stimulation, genome wide expression profiling was performed and an explorative-network based method applied for analysing the data generated (Chapter-4). Although transcriptomics data pertaining to interferon stimulation of macrophages is not entirely novel, the network based analysis of it provided an alternative approach to visualise, mine and interpret the output. The analysis revealed overlap in the transcriptional targets of the two classes of interferon, as well as processes preferentially induced by either cytokine; for example MHC-Class II antigen processing and presentation by IFN-γ, and an anti-proliferative signature by IFN-β. To further investigate the contribution of individual proteins towards generating the type-I (IFN-β) response, short interfering RNA (siRNA) were employed to repress the expression of selected target genes. However in macrophages and other cells equipped with pathogen detection systems the act of siRNA trasfection can itself induce a type-I interferon response. It was therefore necessary to contend with this autocrine production of IFN-β and optimise an in vitro assay for studying the contribution of siRNA induced gene-knock downs to the interferon response (described in Chapter-5). The final assay design incorporated LPS stimulation of the macrophages, as a means of inducing IFN-β autonomously of the transfection induced type-I response. However genome-wide expression analysis indicated the targeted gene knock-downs did not perturb the LPS response in macrophages on this occasion. The optimisation process underscored the complexities of performing siRNA gene knockdown studies in primary macrophages. Furthermore a more thorough understanding of the transcriptional response of macrophages to stimulation by interferon or by LPS was required. Therefore the final investigations of this thesis (Chapter-6) explore the transcriptional changes over a 24 hour time-course of macrophage activation by IFN-β, IFN-γ, or LPS and the contribution of the macrophage pathway model in interpreting the response to the three stimuli. Taken together the work described in this thesis highlight the advances to be made from a systems-based approach to visualisation, modelling and analysis of macrophage signalling.
24
Fransson, Jennifer. "Macrophage activation profiles of multiple sclerosis patients." Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS106.pdf.
Full textAbstract:
La sclérose en plaques (SEP) est une maladie inflammatoire neurodégénérative où l’invasion des cellules immunitaires dans le système nerveux central (SNC) entraîne la destruction de la myéline. Les macrophages, comprenant les cellules microgliales du SNC, sont majoritaires dans les lésions de la SEP. Nous avons modélisé l'activation des macrophages de patients SEP afin de définir quelles propriétés intrinsèques vont diriger leur contribution au développement ou à la réparation de la lésion. Les profils fonctionnels et transcriptomiques des macrophages de donneurs sains et de patients SEP ont été examinés suite à des stimuli activateurs. Les macrophages de patients SEP reproduisent plusieurs aspects observés dans les lésions inflammatoires et présentent une amplitude de réponse plus restreinte que les macrophages de donneurs sains. Grâce à une méthode d'identification des gènes régulateurs construit à partir d’un réseau prédéfini d'interactions géniques, nous avons identifié des gènes clés, pertinents d’un point de vue biologique et pathologique, dont la modulation permettrait de modifier une grande partie du réseau dérégulés. En utilisant un modèle murin humanisé, nous avons également noté que les effets modulateurs des lymphocytes de patient SEP sur la remyélinisation se fait par l’intermédiaire du contrôle de l'activation des macrophages. Les résultats de cette thèse démontrent que la contribution des macrophages à l’environnement inflammatoire reflète l'hétérogénéité clinique des patients. Des recherches futures utilisant ces modèles pourraient être utiles à la fois pour développer de nouveaux traitements et pour prévoir les effets potentiels pour chaque patient<br>Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease in which infiltration of immune cells in the central nervous system (CNS) leads to myelin destruction. Macrophages, including the CNS-resident microglia, are prevalent in MS lesions. We propose that models of macrophage activation based on MS patient leukocytes can provide information on the intrinsic capacities of macrophages to participate to lesion formation and repair. The functional and transcriptomic profiles of MS patient and healthy control monocyte-derived macrophages were examined after exposure to activating stimuli. MS macrophages reproduced several aspects of the inflammatory lesion, and displayed a limited amplitude of response to activating stimuli. We also developed a method to identify key regulators in networks of several altered genes. This was done according to a pre-defined network of gene interactions. Testing a pro- inflammatory network for the possibility to control genes that are dysregulated in MS, we identified biologically and pathologically relevant genes as key drivers, supporting the framework of the method. Using a humanized mouse model of remyelination, we also noted that the remyelination- modulating effects of patient lymphocytes are mediated through the activation of macrophages. In conclusion, the results of this thesis provide evidence that macrophages contribute to an inflammatory environment, and that patient heterogeneity in both lymphocytes and macrophages impact this contribution. Further research using these and similar models could be useful for both developing new treatments and predicting effects for each patient
25
Finlay, Siân. "Modulation of macrophage phenotype using adenoviral transfection." Thesis, University of Aberdeen, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409252.
Full textAbstract:
The initial aim of this study was to examine the nature of the interaction between adenovirus and transfected macrophage, and to characterise the molecular mechanisms underlying macrophage response to adenoviral infection. Results showed that adenoviral transfection activated macrophages, promoting production of pro-inflammatory mediators and priming an enhanced response to other inflammatory stimuli. Activation was dependent on the nuclear factor kappa B (NF<span style='font-family:Symbol'>kB) signalling pathway, which was activated within two hours of transfection, and could be prevented using an inhibitory adenovirus which blocked NF<span style='font-family:Symbol'>kB signalling. The ultimate phenotype of the transfected macrophage was determined both by non-specific viral activation and by the properties of the transgene expressed. The second aim of this research was to investigate the effect of the local cytokine milieu on transgene expression in vitro. Results showed that transgene expression under the control of two different promoter constructs was subject to regulation by pro-inflammatory mediators, by mechanisms at least partly dependent on the NF<span style='font-family:Symbol'>kB signalling pathway. the results have important implications for the use of these promoters in gene therapy applications where the gene of interest is delivered into an inflammatory environment. The final stage of the project focused on the use of transfected macrophages in vivo, in a rat model of glomerulonephritis. Results showed that transfected macrophages expressing the anti-inflammatory cytokine IL-4 localised with enhanced efficiency to inflamed glomeruli after intra-renal artery injection of the mechanisms for this were examined. Better understanding of the mechanisms which promote localisation may ultimately permit the design of genetically-modified macrophages which selectively target sites of injury for delivery of anti-inflammatory cytokines.
26
Whited, Joshua. "Biomimetic Macromolecules for Macrophage Targeting and Modulation." Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1525886398877844.
Full text
27
Wojciechowski, Wojciech. "Molecular mechanism of IFN-[gamma]-induced macrophage activation." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37667.
Full textAbstract:
Macrophages are considered as one of the early effector cells involved in the immunological response against infection. Following macrophages interaction with pathogens, macrophages become activated and attempt to eliminate the invader. Interferon gamma (IFN-gamma) is one of the most important activators of macrophage function. In macrophages IFN-gamma is promoting the expression of major histocompatibility complex class II (MHC-II) molecules and other proteins directly involved in the process of containing infection.<br>The effect of the Nramp1, on macrophage function is investigated in this thesis. Nramp1 has been shown to determine the resistance or susceptibility of mice to infections with several intracellular microorganisms, including Mycobacterium bovis BCG. Although the precise mechanism of Nramp1 action is unknown, there are several well-established effects associated with the Nramp1. In general, it has been shown that macrophages derived from mice susceptible to infections with M. bovis BCG are less efficient in the production of nitric oxide (NO), reactive oxygen intermediates (ROI), TNF-alpha, and MHC-II antigens in response to IFN-gamma.<br>Using macrophage cell lines derived from mice that are either resistant (B10R) or susceptible (B10S) to M. bovis BCG infection, we have demonstrated that lower levels of IFN-gamma-induced expression of MHC-II antigens is correlated with less efficient phosphorylation of the STAT1 protein in B10S macrophages compared to B10R macrophages. We have shown that low levels of MHC-II expression in B10S macrophages correlate with less efficient expression of CIITA (Class II Transactivator). We have observed that infection of macrophages with M. bovis BCG has an inhibitory effect on both CIITA and MHC-II expression in macrophages stimulated with IFN-gamma.<br>We have also studied the effect of lipopolysaccharide (LPS) on MHC-II expression in macrophages. We have found that the inhibitory effect of LPS on CIITA gene transcription does not involve changes in the binding of STAT1 to CIITA promoter IV. We have also demonstrated that unlike M. bovis BCG, the inhibitory effect of LPS on MHC-II expression is mediated by Toll-like receptor 4 (TLR4). In addition, we have shown that inhibitory effects of both LPS and M. bovis BCG depend on the adaptor protein MyD88.<br>We have also analyzed the regulation of IFN-gamma- or/and LPS-stimulated expression of TLR2 in macrophages. We have shown that regulation of TLR2 expression by IFN-gamma depends on TLR4 expression. We have also determined that the phenol extractable fraction present in the commercial preparations of endotoxins from Gram-negative bacteria is able to synergize with IFN-gamma and activate TLR4-deficient macrophages.<br>Overall, we believe that these studies significantly contribute to the understanding of the molecular mechanism of the process of macrophage activation.
28
Sester, David Peter. "Mechanisms of macrophage activation by bacterial/CpG DNA /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17063.pdf.
Full text
29
Contreras, Ana Paulina. "Modulation of macrophage nitric oxide production by hemozoin." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100786.
Full textAbstract:
Malaria is one of the most serious human infectious diseases. To date, the collection of studies suggest that the disease is determined by transmission dynamics and host age altogether with host genetics and immunological responses. The precise and direct contribution of parasite components to the activation of such immunological responses has not been fully unravelled. In addition to a role proposed for plasmodial GPI, different lines of evidence suggest that hemozoin (HZ) could also be a potential inflammatory agent. The role of HZ in the modulation of immune responses has remained a polemic subject, making it difficult to describe the contribution of this molecule in pathogenesis of malaria. However, our previous laboratory studies, suggest that HZ has a pro-inflammatory role. For this reason, our study was designed to further define the contribution of HZ to the pro-inflammatory events related to malaria immunopathology, and to identify the intracellular signals underlying the up-regulatory effects of HZ in the macrophage, one of the major sources of inflammatory mediators in malaria. In order to do that, we used a chemically characterized synthetic version of the native PfHZ, rcHZ; and evaluated its effects on macrophage nitric oxide (NO) production. Our first approach was to compare the effects of rcHZ with other morphologically different versions of this molecule (aHZ and scHZ) alone or in combination with IFN-gamma on macrophage NO production. In a second approach, we evaluated if the presence of serum proteins plays a role in the increased IFN-gamma induced-NO production by rcHZ. In the third part of our study, we explored if rcHZ is able to increase NO production by macrophages when incubated in combination with a molecule from another pathogen, such as gram-negative bacteria lipopolysaccaride (LPS). The present study is a functional study that uses a synthetic and morphologically identical version of the native PfHZ. Our results suggests that intrinsic physical characteristics, such as shape and size; presence of host serum proteins, and presence of other pathogenic molecules, are important determinants for the macrophage response to HZ in the context of NO production. Besides, it describes part of the signaling pathways that are involved, which may contribute in the future, not only to understand mechanisms of regulation; but also, to find new therapeutic targets against malaria.
30
Giles, Katherine Mary. "Glucocorticoid modulation of macrophage phagocytosis of apoptotic neutrophils." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/23016.
Full text
31
Longbrake, Erin Elisabeth. "Consequences of differential macrophage activation after spinal cord trauma." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1177686458.
Full text
32
Chow, Nancy Ann-Marie. "TNF gene expression in macrophage activation and endotoxin tolerance." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11231.
Full textAbstract:
TNF is an inflammatory cytokine that plays a critical role in the acute phase response to infection, and its dysregulation has been implicated in the pathology of several inflammatory and autoimmune disorders. TNF gene expression is regulated in a cell type- and inducer-specific manner that involves chromatin alterations at both the TNF promoter and distal DNase I hypersensitive (DH) sites within the TNF/LT locus. While the mechanisms underlying TNF gene activation in monocytes/macrophages and T cells have been studied intensively, the mechanisms of enhanced, repressed, and restored TNF gene expression in the context of classical macrophage activation and endotoxin tolerance remain largely unknown. We set out to understand how TNF gene expression is modulated during these biological processes by characterizing the chromatin environment of the TNF/LT locus.
33
Longbrake, Erin E. "Consequences of differential macrophage activation after spinal cord trauma." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1177686458.
Full text
34
Oda, Tomoyuki. "Activation of hypoxia-inducible factor 1 during macrophage differentiation." Kyoto University, 2007. http://hdl.handle.net/2433/135669.
Full text
35
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.
Full textAbstract:
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.<br>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.<br>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.<br>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$, a potential secondary signal was associated with decidual macrophage activation, NO production, and subsequent embryo loss.
36
Haddad, Elias K. "Study of the role of macrophage activation and macrophage derived cytotoxic factors in early embryo loss." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ29928.pdf.
Full text
37
Séguin, Rosanne. "Modulation of macrophage functions by components of Entamoeba histolytica." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40247.
Full textAbstract:
Entamoeba histolytica is a protozoan parasite and the causative agent of amebiasis. Activated macrophages are the main host effector cells in host defence against E. histolytica, through the production of nitric oxide (NO) which is cytotoxic for the parasite. NO is upregulated by tumor necrosis factor-alpha (TNF-$ alpha$) produced by macrophages. The objective of this study was to determine the effect of amebic components on TNF-$ alpha$ and NO production by macrophages. Soluble E. histolytica proteins stimulated naive macrophages for enhanced TNF-$ alpha$ mRNA expression through PKC signal transduction. E. histolytica-induced TNF-$ alpha$ mRNA expression was unstable, and macrophages pretreated with E. histolytica proteins expressed reduced levels of TNF-$ alpha$ mRNA in response to LPS or IFN-$ gamma$ + LPS. In contrast, the purified galactose-adherence lectin (Gal-lectin) of E. histolytica stimulated naive macrophages for stable TNF-$ alpha$ mRNA expression and protein production. Furthermore, IFN-$ gamma$ primed macrophages produced TNF-$ alpha$ and NO in response to the Gal-lectin. Naive macrophages exposed to Gal-lectin + IFN-$ gamma$ were activated to kill E. histolytica trophozoites in vitro by NO. Anti-lectin monoclonal antibodies that recognize non-overlapping epitopes of the kDa heavy subunit of the Gal-lectin identified amino acids 596-1082 as important in mediating amebic adherence to target cells and TNF-$ alpha$ mRNA induction in macrophages. Likewise, a region between amino acids 596-818 of the 170 kDa Gal-lectin, in conjunction with IFN-$ gamma$, activated macrophages for TNF-$ alpha$ and NO production and amebicidal activity. This research demonstrates the immunogenic potential of the E. histolytica Gal-lectin and the critical regions that could be used as a subunit vaccine candidate against amebiasis.
38
Tan, Thomas Chin Che. "Modulation of fractalkine receptor (CX3CR1) activation." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555309.
Full textAbstract:
The fractalkine receptor (CX3CRl) has been implicated in a range of diseases involving an inflammatory component. While CX3CRl appears to play an anti-inflammatory role in certain conditions it has also been reported to promote inflammation. The mechanism behind this pleiotropic effect has not been studied. The hypothesis of this thesis predicts that functional responses following CX3CRl activation depend on the local cytokine environment and the molecular form wherein fractalkine is presented. The pleiotropic role of CX3CRl furthermore suggests that compounds that inhibit or activate CX3CRl may be therapeutically useful. Aiming at developing such compounds, a series of fractalkine mimicking recombinant proteins were designed, some of which specifically inhibited fractalkine induced calcium signalling in CX3CRl expressing primary cells and cell lines. Surprisingly these same constructs were able to induce chemotaxis in a CX3CRl dependent manner, indicating that these constructs inhibit some signalling pathways while activating others. The hitherto known pathway engaged by fractalkine is pertussis toxin sensitive. Multivalent fractalkine was found to induce migration in a valency dependent but pertussis toxin insensitive manner. Furthermore only surface bound fractalkine, but not soluble monovalent fractalkine, was found to stimulate human cell mediated cytotoxicity in a pertussis toxin insensitive manner. These results are consistent with the presence of an alternative CX3CRl activation pathway which may constitute the molecular basis that allows CX3CRl + cells to differentiate between membrane tethered and soluble fractalkine. The significance of the local inflammatory environment was also investigated. To this end IL-6 was found to transiently alter the migrational potential of a microglial cell line in response to soluble fractalkine, suggesting that at least for these cells CX3CRl responses can be modified by other cytokines. In summary this thesis work introduces useful molecular tools and novel concepts towards the understanding of CX3CRl activation and its pleiotropic outcome.
39
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.
Full text
40
Gross, Antoine. "Activation et inhibition du macrophage lors de l'infection par "Brucella"." Montpellier 2, 1998. http://www.theses.fr/1998MON20216.
Full textAbstract:
Brucella est responsable d'infections chroniques chez l'homme et les ruminants domestiques ; elle n'infecte pas naturellement la souris. Afin d'analyser les phenomenes permettant a brucella d'infecter et de se maintenir chroniquement chez l'homme, nous avons etudie et compare differents processus impliques dans l'interaction de brucella avec les macrophages humains et murins a l'interieur desquels elle se multiple. Cette these presente quatre aspects de cette problematique : 1) nous avons caracterise une induction de la inos lors de l'infection du macrophage murin par brucella et montre que no est un composant de l'activite microbicide contre cette bacterie. Contrairement a la cellule murine, le macrophage humain dans lequel une activite inos fonctionnelle a ete mise en evidence, ne produit pas de no lorsqu'il est infecte par brucella. 2) l'etude des cytokines secretees au cours de l'infection revele que brucella inhibe specifiquement la secretion de tnf- par le macrophage humain. Ce phenomene n'est jamais observe dans le modele murin. Cette activite inhibitrice ne conduit pas a une desactivation complete de la cellule infectee. L'inhibition de la secretion du tnf resulte d'un facteur soluble pouvant etre libere dans le milieu de culture et considere comme un facteur de virulence chez l'homme. 3) malgre l'absence de tnf-, l'infection par brucella confere une resistance a l'apoptose aux monocytes/macrophages humains. Cette resistance implique un processus suppletif a l'absence de tnf-, favorisant la survie de la cellule hote et le developpement de la bacterie. 4) les cannabinoides affectent le macrophage en modulant la production de cytokines. Stimules par sr 141716a, un antagoniste des recepteurs cb1 aux cannabinoides, les macrophages humains controlent la multiplication intracellulaire de brucella. Toutefois, cet effet n'implique pas une reactivation de la production de tnf- et est retrouve lors de l'infection de macrophages murins.
41
Tabata, Yasuhiko. "Macrophage phagocytosis of polymer microspheres and antitumor activation of macrophages." Kyoto University, 1987. http://hdl.handle.net/2433/74704.
Full text
42
Sundling, Niklas, and Lisa Lü. "Characterization of Macrophage Activation Induced by Leukotoxin from Aggregatibacter actinomycetemcomitans." Thesis, Umeå universitet, Institutionen för odontologi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-143900.
Full textAbstract:
ABSTRACT Aggregatibacter actinomycetemcomitans (Aa), is a gram-negative, facultative anaerobe, non-motile coccobacilli colonizing the human oral cavity and is strongly associated with localized aggressive periodontitis (LAP). Aa possesses several virulence mechanisms, among others; Lipopolysaccharide (LPS), an endotoxin found in the outer membrane of Aa and Leukotoxin (LtxA), an exotoxin attached to the bacterial cell surface or in outer membrane vesicles and which has been correlating with periodontal disease mostly. LtxA specifically targets human leukocytes, causing imbalance in the host inflammatory response. It is involved in the activation of a cellular pathway, starting with ATP release from the cell, possibly through Pannexin-1(Panx-1) channels, Caspase-1 activation and release of bioactive interleukin-1β (IL-1β) from leukocytes. In the case of periodontitis, inflammatory cytokines like IL-1β will stimulate periodontal tissue breakdown. The aim of the present study was to examine the involvement of Panx-1 in LtxA induced activation and cytotoxicity of human macrophages. To determine viability of the macrophages the release of LDH and the accumulation of neutral red was quantified. The release of IL-1β was analysed by ELISA analyses of the cell culture supernatants. Results showed that macrophages treated with Cbx and exposed to LtxA was still sensitive to LtxA, but showed a decrease in the IL-1β release. In opposite, macrophages exposed to LPS showed increased IL-1β release in presence of Cbx. The conclusion of our study is that Panx-1 channels are partially involved in the cellular pathway leading to IL-1β release on LtxA exposed cells.
43
Tejle, Katarina. "Leishmania donovani Lipophosphoglycan : Modulation of Macrophage and Dendritic Cell Function." Doctoral thesis, Linköping : Univ, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-6527.
Full text
44
Snyder, Ellen Amanda Flood Patrick M. "[beta]2-adrenergic receptor modulation of macrophage inflammatory mediator production." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1344.
Full textAbstract:
Thesis (M.S.)--University of North Carolina at Chapel Hill, 2007.<br>Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Master of Science in the Curriculum of Oral Biology." Discipline: Oral Biology; Department/School: Dentistry. On title page, [beta] appears as Greek character and 2 appears as subscript.
45
Raborn, Erinn Shenee. "Cannabinoid Modulation of Chemotaxis of Macrophages and Macrophage-like Cells." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1333.
Full text
46
Degboé, Yannick. "Modulation thérapeutique du phénotype du macrophage dans la polyarthrite rhumatoïde." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30085/document.
Full textAbstract:
La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire chronique le plus fréquent. Cette maladie est caractérisée par une auto-immunité et une synovite hypertrophique, responsables d'une destruction des articulations périphériques. Les macrophages contribuent aux phénomènes inflammatoires de la PR. Ces cellules peuvent présenter différents états d'activation ou " polarisation ", réversibles, dépendant de leur environnement, notamment cytokinique. Les biothérapies (bDMARDs) ont représenté une avancée majeure dans la prise en charge des manifestations inflammatoires des formes sévères de PR. Toutefois, peu d'études ont évalué si ce bénéfice était lié à une action spécifique sur le macrophage. L'objectif de ce travail de transversal était : (i) d'évaluer in vitro l'effet des principales biothérapies de la PR (anti-TNF : etanercept, adalimumab, certolizumab ; anti-IL- 6R : tocilizumab ; CTLA4-Ig : abatacept) sur la différenciation et l'activation de macrophages dérivés de monocytes issus de patients atteints de PR et de sujets sains, (ii) d'identifier des marqueurs de polarisation du macrophage, corrélés à l'activité de la maladie (DAS28). Parmi les bDMARDs évalués, seuls les anti-TNF ont montré une action sur la polarisation des macrophages. En contexte de différenciation avec M-CSF, les bDMARDs anti-TNF ont induit un biais vers une polarisation non inflammatoire dite alternative. En contexte d'activation inflammatoire, les bDMARDs anti-TNF ont induit une préservation sélective des marqueurs de polarisation liés à l'IL-10 (CD16, CD163, MerTK) et une inhibition des marqueurs inflammatoires (CD40, CD80). Nous avons montré que ce changement phénotypique s'accompagnait : (i) d'un changement fonctionnel concordant avec une polarisation induite par l'IL-10, (ii) d'une inhibition de la production des cytokines de l'inflammation (TNF, IL-6, IL-12), (iii) et d'une majoration de la phagocytose. Nous avons montré que ce mécanisme était dû à une production précoce d'IL-10 et dépendant de STAT3. De plus, nous avons pu montrer que le certolizumab, un anti-TNF, induisait une réponse anti-inflammatoire, impliquant le facteur de transcription NRF2 (nuclear factor erythroid-2-related factor 2), un régulateur central dans la réponse au stress oxydatif. Enfin, nous avons observé que l'expression de CD16, à la surface des macrophages non activés, était corrélée négativement à l'activité de la PR. Ces travaux concourent à montrer l'intérêt du ciblage du macrophage dans la PR et nous ont d'identifier de potentielles cibles théranostiques dans le traitement de la PR par anti-TNF<br>Rheumatoid arthritis (RA) is the most frequent chronic inflammatory rheumatism. This disease is characterized by an auto-immunity and a hyperplasic synovitis, both responsible for peripheral joints destruction. Macrophages contribute to inflammatory aspects of RA. This cell type can present various states of activation or "polarization", reversible and dependent on its environment, notably cytokines. Biologics (bDMARDs) represented a revolution in severe RA treatment. However, data regarding their specific action on macrophage are scarce. The aim of our translational work was: (i) to assess the in vitro effect of RA bDMARDs (anti-TNF: etanercept, adalimumab, certolizumab; anti-IL-6R: tocilizumab; CTLA4-Ig: abatacept) on the phenotype of monocytes-derived-macrophages from RA patients and healthy volunteers, during differentiation and activation phases, (ii) to identify polarization markers correlated with disease activity (DAS28). Among bDMARDs, only anti-TNF modulated macrophage polarization. During differentiation, anti-TNF bDMARDs induced a bias toward the so-called alternative non-inflammatory polarization. In inflammatory context, anti-TNF bDMARDs induced a selective preservation of markers associated with IL-10 (CD16, CD163, MerTK) and an inhibition of inflammatory markers (CD40, CD80). We showed that these changes in phenotype were associated with changes in functions consistent with: (i) a polarization induced by IL10, (ii) a decrease in inflammatory cytokines production (TNF, IL-6, IL-12), (iii) and an increase in phagocytosis. We showed that this mechanism was dependant on early IL-10 production and STAT3 signaling. Moreover, we have showed that certolizumab, an anti-TNF agent, induced an anti-inflammatory response, implicating the transcription factor NRF2 (nuclear factor erythroid-2- related factor 2), a central regulator of the response to oxidative stress. We observed that CD16 expression on non-activated macrophages was negatively correlated with RA activity. This work contributes to demonstrate the relevance of macrophage targeting in RA, and enabled us to identify theranostic targets for RA treatment with anti-TNF bDMARDs
47
Nzoumbou-Boko, Romaric. "Caractérisation d’une voie Immunomodulatrice impliquant l’arginase dans les Trypanosomoses." Thesis, Bordeaux 2, 2013. http://www.theses.fr/2013BOR22053/document.
Full textAbstract:
Une nouvelle voie d’immunomodulation, l’induction de l’arginase par les trypanosomes chez leurs hôtes, a été identifiée et caractérisée. Pour éviter la réponse cytotoxique de l’activation « classique » M1 des macrophages et bénéficier de leur activation « alternative » M2, les parasites induisent l’arginase, qui produit la L-ornithine, indispensable à leur développement. Cette voie d’immunomodulation mise en évidence chez la souris infestée par son parasite naturel, Trypanosoma musculi, est également présente dans d’autres trypanosomoses, en particulier la trypanosomose humaine africaine (THA). Une augmentation de l’arginase, retrouvée dans le sérum de patients trypanosomés, se normalise après un traitement efficace. T. brucei gambiense, parasite de l’homme, induit l’arginase au niveau des macrophages murins et des leucocytes humains. T. lewisi, parasite du rat, induit également l’arginase. Au cours de leur longue coévolution avec leurs hôtes, les trypanosomes extracellulaires ont sélectionné un procédé favorisant leur croissance, l’induction de l’arginase, par des facteurs d’excrétion/sécrétion. Nous avons produit un anticorps monoclonal dirigé contre ce facteur inducteur. Il bloque l’induction de l’arginase par T. musculi in vitro et in vivo. Chez la souris infectée, son injection diminue considérablement la parasitémie. Il a permis l’identification du facteur inducteur, une kinésine orpheline. Cet anticorps, inhibant l’induction de l’arginase par différents trypanosomes, reconnaîtrait une région conservée de la kinésine induisant l’arginase. Cette kinésine se lie à des récepteurs de la membrane des macrophages. In vitro, l’addition de mannose à des co-cultures macrophages-parasites bloque l’induction de l’arginase et la multiplication des parasites. Chez la souris infestée par T. musculi, l’injection de mannose diminue la parasitémie, qui est également réduite chez les souris Mrc1-/-, KO pour le récepteur mannose. L’utilisation de molécules ciblant la voie inductrice de l’arginase et/ou ce récepteur peut représenter une nouvelle approche thérapeutique dans les trypanosomoses<br>Arginase induction, a mechanism of immunomodulation elaborated by trypanosomes has been identified. To avoid cytotoxic classical M1 macrophage activation, trypanosomes induce alternative M2 macrophage activation, which leads to L-ornithine production, essential for parasite growth. This immunomodulation pathway has been evidenced in a natural murine trypanosomiasis provoked by Trypanosoma musculi. This mechanism is also evidenced in human African trypanosomiasis (HAT). An increase in serum arginase is measured in HAT patients. A return to normal values is obtained after an efficacious treatment. Trypanosoma brucei gambiense, the causative agent of HAT, induces arginase in mouse macrophages and human leucocytes. T. lewisi, a rat parasite, also induces macrophage arginase.During host-parasite co-evolution, extracellular trypanosomes have selected a growth promoting mechanism, macrophage arginase induction by excreted secreted factor (ESF). We have produced a monoclonal antibody which inhibits trypanosome-induced arginase. This antibody blocks in vitro and in vivo T. musculi-induced arginase. Its injection into infected mice provokes a decrease in parasite load. This monoclonal antibody has allowed the identification of an orphan kinesin as the arginase inducing factor. The arginase inducing region of kinesin seems conserved among extracellular trypanosomes. Kinesin binds to macrophage membrane receptors. In vitro, addition of mannose to macrophage-parasite cocultures blocks arginase induction and parasite multiplication. Mannose injection decreases parasite load in infected mice. Compared to WT mice, parasite load is highly reduced in infected Mrc1 -/- KO mice. In trypanosomiasis, molecules targeting arginase pathway and/or mannose receptor, highly conserved in evolution, might represent new therapeutic approaches
48
Carreras, Sureda Amado 1986. "Modulation of T lymphocite activation by ORMDL3." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/319714.
Full textAbstract:
Genome wide association studies (GWAS) have pointed out ORMDL3 gene as a risk factor for several proinflammatory and autoimmune diseases. The protein encoded by this gene belongs to a family of transmembrane proteins of the endoplasmic reticulum involved in calcium homeostasis and cellular lipid metabolism. The driving force behind this work was the compelling idea of finding out a precise mechanism for the pathological association of this protein. This thesis explores the potential role of ORMDL3 in T lymphocytes focusing on the activation process. Thus, we have demonstrated that calcium signaling and activation of T cells are influenced by the expression levels of ORMDL3. Besides, we have shown that inherited components of our genome modify ORMDL3 expression levels and lymphocyte physiology. Finally, we have characterized the molecular complex formed by ORMDL proteins. Altogether, this work allows a better understanding of the pathophysiology associated to ORMDL3 and its linkage with the immune system.<br>Estudis d’associació genètica ample han apuntat cap al gen ORMDL3 com a factor de risc per diverses malalties pro-inflamatòries i autoimmunes. La proteïna codificada per aquest gen pertany a una família de proteïnes transmembrana del reticle endoplàsmic involucrada en l’homeòstasi de calci i en el metabolisme lipidic cel•lular. El motiu que ens va impulsar a dur a terme aquest treball era la idea de trobar el mecanisme darrere les associacions a patologia per aquesta proteïna. Aquesta tesis explora el rol potencial d’ORMDL3 en limfòcits T, amb èmfasi al procés d’activació. Així doncs hem demostrat que la senyalització de calci i la activació de cèl•lules T es veu influenciada pels nivells d’expressió d’ORMDL3. A més hem demostrat que components del nostre genoma modifiquen els nivells d’expressió d’ORMDL3 i la fisiologia limfocitària. Per acabar hem caracteritzat el complex molecular de les proteïnes ORMDL. En conjunt, aquest treball permet una millor comprensió de la fisiopatologia associada a ORMDL3 i la seva relació amb el sistema immune
49
Lisowski, Zofia Maria. "Targeting the macrophage in equine post-operative ileus." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33191.
Full textAbstract:
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.
50
Schroder, Kate. "Mechanisms of IFN[gamma] priming of macrophage activation by CpG DNA /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18684.pdf.
Full text