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Title: Macrophage chemotaxis to apoptotic cells
Author: Truman, Lucy
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The CD14 knockout mouse (CD14-/-) was observed to have increased numbers of free apoptotic cells in the thymus. It was hypothesised that this was due to a defect in macrophage clearance of dying cells. In vitro assays revealed that macrophages from the CD14-/- mouse had a partial defect in the phagocytosis of apoptotic cells. Clearance also involves macrophage movement towards the apoptotic corpse. Therefore, it was hypothesised that, in addition to a phagocytosis defect, CD14-/- had impaired chemotaxis to apoptotic cells. An in vitro transmigration assay was developed using the B-cell line “Mutu” as a source of apoptotic cells. In this assay, monocytes and macrophages, but not neutrophils, migrated preferentially to apoptotic Mutu, and chernotaxis correlated to phosphatidylserine exposure on apoptotic cells. Chemotaxis was abolished when Mutu were transfected with the anti-apoptotic protein bcl-2. Although CD14 was up regulated on the surface of the migrating macrophages, experiments with knockout cells revealed that chemotaxis did not require either CD14 or the scavenger receptor CD36. Experiments using a viral chemokine antagonist (vMIPII) suggested that fractalkine (CX3CL1) was a candidate chemokine released from dying cells. Fractalkine was expressed by apoptotic cells and in chemotaxis assays CX3CL1 competitively inhibited macrophage migration to apoptotic cells but not to CCL5 (RANTES). Monoclonal antibodies that blocked the chemokine domain of CX3CL1 also inhibited macrophage chemotaxis to apoptotic cells. This is the first demonstration of the involvement of a known chemokine receptor in the clearance of apoptotic cells. In this novel process, cells dying by apoptosis release fractalkine that recruits macrophages primed to efficiently engulf the cell corpse.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available