The pro-remyelination properties of microglia in the central nervous system

Microglia are resident macrophages of the CNS that are involved in its development, homeostasis and response to infection and damage. Microglial activation is a common feature of neurological disorders, and although in some instances this activation can be damaging, protective and regenerative functions of microglia have been revealed. The most prominent example of the regenerative functions is a role for microglia in supporting regeneration of myelin after injury, a process that is critical for axonal health and relevant to numerous disorders in which loss of myelin integrity is a prevalent feature, such as multiple sclerosis, Alzheimer disease and motor neuron disease. Although drugs that are intended to promote remyelination are entering clinical trials, the mechanisms by which remyelination is controlled and how microglia are involved are not completely understood. In this Review, we discuss work that has identified novel regulators of microglial activation — including molecular drivers, population heterogeneity and turnover — that might influence their pro-remyelination capacity. We also discuss therapeutic targeting of microglia as a potential approach to promoting remyelination. In this Review, Lloyd and Miron consider how regulation of microglial activation influences the ability of microglia to promote remyelination in the CNS. They also discuss the potential to exploit the pre-remyelination properties of microglia to treat multiple sclerosis and other demyelinating diseases. Key points Microglia can support remyelination in the CNS after injury via clearance of debris, secretion of growth factors and cytokines and modulation of the extracellular matrix. Novel drivers of pro-remyelination microglia activation and function have recently been identified. Microglia exhibit heterogeneity in their transcriptome, protein expression, proliferation and function within and between CNS regions, which might influence their pro-remyelination capacity. Active microglia turnover occurs under homeostatic conditions in both the human and rodent CNS; turnover is altered with disease and ageing and can be experimentally targeted to alter pathological outcome. Although no microglia-specific drug targeting strategy currently exists, microglia might be targeted by pro-remyelination drugs that are currently in clinical trials. Challenges in developing microglia-targeted drugs include understanding microglial heterogeneity, avoiding pro-inflammatory effects, developing