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Receptor-mediated phagocytosis of myelin by macrophages and microglia

Mosley, Karen; (1997) Receptor-mediated phagocytosis of myelin by macrophages and microglia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Demyelination is a major pathological feature of multiple sclerosis (MS), resulting in the formation of lipid laden microglia (MG) and macrophages (MØ), suggesting the involvement of receptor-mediated myelin phagocytosis. Myelin is phagocytosed by MG, and to a lesser extent, peritoneal macrophages, in a dose and time dependent manner. Opsonisation of the myelin with specific anti-myelin antibodies significantly increases phagocytosis, particularly by MØ. The uptake of both myelin and opsonised myelin is inhibited to a similar extent by zymosan, anti-CR3 antibody, mannose and melibiose, opsonised erythrocytes, peroxidase anti-peroxidase, aggregated IgG and oxidised low density lipoprotein (OxLDL), implicating the involvement of the complement, lectin, Fc and scavenger receptors in myelin phagocytosis. Therefore, although the difference in uptake between myelin and opsonised myelin would suggest that the FcR plays a significant role in phagocytosis, these inhibition studies suggest that a range of receptors contribute, which may negate the requirement for antibody opsonisation to fuel demyelination. The uptake of myelin and opsonised myelin by MG and MØ is stimulated by interferon-y and inhibited by transforming growth factor-β and results in increased nitric oxide and decreased superoxide production, particularly with opsonised myelin. The release of reactive oxygen intermediates could contribute to extracellular myelin damage, such as oxidation. Oxidation of these membranes leads to the aggregation and loss of integrity of myelin proteins. This results in a decrease in the binding of anti-myelin antibodies, and a reduction in the phagocytosis observed with opsonisation. Competition for the scavenger receptor with OxLDL is enhanced after myelin oxidation and modified myelin has been identified in the spinal cords of rats during the clinical stages of experimental allergic encephalomyelitis (EAE). These results suggest that the extraneous metabolic modification of the myelin, in addition to receptor-mediated phagocytosis, could enhance the degree of demyelination.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Receptor-mediated phagocytosis of myelin by macrophages and microglia
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Multiple sclerosis
URI: https://discovery.ucl.ac.uk/id/eprint/10104724
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