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Title: Cellular and molecular mechanisms underpinning microglial activation during remyelination
Author: Lloyd, Amy Frances
ISNI:       0000 0004 7969 1069
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Failed regeneration of myelin in the central nervous system (CNS) contributes to axon loss/dysfunction in prevalent neurodegenerative disorders, for which there is an unmet need for effective therapies. Previous work from this lab has demonstrated that remyelination requires a transition in microglia activation from pro-inflammatory (inducible nitric oxide synthase (iNOS)+) to pro-regenerative (arginase-1 (Arg-1+)). However, the mechanisms underpinning microglia activation remain unknown, and the assumption that in situ tissue macrophages can transition in activation state has never been substantiated. Here, unexpectedly it is revealed that microglia activation during remyelination is driven by their death and subsequent repopulation. More specifically, pro-inflammatory microglia undergo controlled necrosis (necroptosis), followed by repopulation via residual microglia and CNS-resident Nestin+ cell differentiation into microglia. Blocking necroptosis prevented microglial death and maintained their pro-inflammatory (iNOS+) activation, which consequently hindered remyelination. In human brain tissue, necroptosing and repopulating microglia were only significantly increased in white matter lesions with a high potential for remyelination. These results overturn current assumptions that following injury, microglia simply switch their activation from an initial pro-inflammatory phenotype to become pro-regenerative. Impairment in microglia death and/or repopulation may thus underpin the chronic pro-inflammatory microglia activation associated with failed remyelination in human pathology, highlighting a novel therapeutic strategy in the treatment of chronic inflammatory and neurodegenerative diseases.
Supervisor: Miron, Veronique ; Pollard, Jeffrey ; Williams, Anna Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: remyelination ; microglia ; Multiple Sclerosis ; inflammatory microglia ; inflammatory microglial death