Central nervous system regeneration is driven by microglia necroptosis and repopulation

1.MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK,  2. MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK,  3. Neurosciences Therapeutic Area Unit, GlaxoSmithKline R&D, Stevenage, Herts, UK

Microglia, the resident macrophages of the central nervous system (CNS) are required for remyelination after injury. In progressive multiple sclerosis (MS), remyelination is limited or fails altogether which is considered to contribute to axonal damage and loss that correlates to sensory, motor and cognitive decline. Our previous work showed that dynamic temporal regulation of activation of microglia controls oligodendrocyte progenitor cell (OPC) responses during remyelination, and that microglial activation must undergo a transition from a pro-inflammatory to a pro-regenerative phenotype in order to drive OPC differentiation and remyelination. However the cellular mechanism underpinning this switch is unknown, and may reflect a direct immunomodulation or cell death/ repopulation of microglia. We addressed this question by investigating microglia dynamics during remyelination using an ex vivo brain explant model and an in vivo demyelinating lesion model. Using immunofluorescence and live imaging of a microglia reporter mouse, we observed that activated pro-inflammatory microglia undergo controlled necrosis (necroptosis) followed by a period of repopulation via nestin+ cell differentiation into microglia capable of pro-regenerative functions that drive remyelination. Furthermore, preventing microglial necroptosis maintained the pro-inflammatory microglial phenotype and significantly hindered remyelination. Importantly, active necroptosis and repopulation of microglia was seen in human MS lesions capable of remyelinating, but not in those that could not, suggesting that targeting pro-inflammatory microglia death and repopulation in neurological diseases may represent a novel strategy to dampen chronic CNS inflammation-associated pathology and support a regenerative response.

Funded by: BBSRC CASE Studentship in collaboration with GlaxoSmithKline

* entered into the PhD student poster competition