Abstract
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.
Key points
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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.
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Novel drivers of pro-remyelination microglia activation and function have recently been identified.
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Microglia exhibit heterogeneity in their transcriptome, protein expression, proliferation and function within and between CNS regions, which might influence their pro-remyelination capacity.
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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.
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Although no microglia-specific drug targeting strategy currently exists, microglia might be targeted by pro-remyelination drugs that are currently in clinical trials.
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Challenges in developing microglia-targeted drugs include understanding microglial heterogeneity, avoiding pro-inflammatory effects, developing microglia-specific drug delivery platforms, determining optimal timing of drug delivery and refining tools to monitor microglial responses.
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Acknowledgements
V.E.M. is funded by a Career Development Award from the Medical Research Council and the United Kingdom Multiple Sclerosis Society (MR/M020827/1), as well as from funds from the Medical Research Council Centre for Reproductive Health (MR/N02256/1).
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Nature Reviews Neurology thanks D. Fitzgerald, S. Rivest, M. Stangel and V. W. Yong for their contribution to the peer review of this work.
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V.E.M. has received research funds related to remyelination within the past 5 years from Biogen, BVBioMed, Clene Nanomedicine, GlaxoSmithKline and Rewind Therapeutics.
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Glossary
- Oligodendrocyte progenitor cells
-
(OPCs). A glial subtype derived from neuroepithelium that can differentiate into mature oligodendrocytes, astrocytes and Schwann cells.
- iNOS
-
(Inducible nitric oxide synthase). An enzyme that catalyses the generation of nitric oxide from l-arginine and competes with arginase 1 (ARG1) for the same substrate.
- TNF
-
(Tumour necrosis factor). A pro-inflammatory cytokine that can have deleterious and beneficial effects on the oligodendrocyte lineage.
- CD16–CD32
-
Low-affinity immunoglobulin Fc receptors FcγIIA/B (CD16) and FcγIIIA/B (CD32); involved in phagocytosis, microorganism toxicity, stimulation of cytokine production and antibody-dependent cell-mediated cytotoxicity.
- ARG1
-
(Arginase 1). An enzyme that catalyses the generation of ornithine and urea from l-arginine and competes with iNOS for the same substrate, thus indirectly reducing production of nitric oxide.
- IGF1
-
(Insulin-like growth factor 1). A growth factor that stimulates oligodendrocyte differentiation and remyelination.
- CD206
-
Also known as mannose receptor. A transmembrane glycoprotein that binds to mannosylated molecules and probably plays a role in clearance of pathogens.
- Repopulation
-
Re-establishment of a cell population following depletion or loss; microglia repopulation following robust depletion (80–99%) can occur within 1 week.
- Single-cell sequencing
-
A next-generation sequencing approach that allows transcriptomic profiling of individual cells, providing information regarding heterogeneity of a population.
- Induced pluripotent stem cells
-
(iPSCs). Pluripotent stem cells derived from reprogramming of somatic cells; iPSC-derived microglia react to inflammatory stimuli and phagocytose in a similar manner to primary microglia.
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Lloyd, A.F., Miron, V.E. The pro-remyelination properties of microglia in the central nervous system. Nat Rev Neurol 15, 447–458 (2019). https://doi.org/10.1038/s41582-019-0184-2
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DOI: https://doi.org/10.1038/s41582-019-0184-2
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