Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.651483
Title: Molecular mechanisms underlying the control of phagocyte clearance of apoptotic cells
Author: Gilles, K. M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Abstract:
The aim of this thesis was to investigate the molecular mechanisms underlying control of macrophage phagocytosis of apoptotic cells. We have demonstrated that exposure of peripheral blood monocytes to the synthetic glucocorticoid dexamethasone “reprograms” monocyte/macrophage differentiation resulting in a macrophage phenotype with a marked augmentation in the phagocytosis of both apoptotic granulocytes and particles opsonized with low levels of IgG. Increase in phagocytic potential was not mediated by increased expression of putative “phagocytic receptors” proposed to be involved in apoptotic cell clearance. In addition dexamethasone augmentation of apoptotic cell uptake could not be inhibited by blockade of receptor function with either soluble competitive ligands or monoclonal antibodies. Dexamethasone treated macrophages were found to have altered morphology and actin organisation. In particular, loss of “podosome” structures was observed, possibly due to decreased recruitment of adhesion signalling molecules pyk2 and paxillin to focal contacts, and decreased expression of p130cas, a key adaptor molecule in integrin signalling. In addition, glucocorticoid treated cells showed increased activity of the Rho-family GTPase Rac, which has been previously shown to be important for phagocytosis and lamellipodia formation. Expression of p130cas and activation of the mitogen activated protein kinase, ERK are required for migration in a number of different cell types. Basal ERK activity was reduced by dexamethasone-treated monocyte/macrophages. We developed an in vitro “wounding” assay and found that despite the absence of basal ERK activity or p130cas expression in dexamethasone-treated macrophages, these cells were able to migrate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.651483  DOI: Not available
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