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Microglia are resident macrophages of the central nervous system that have key functions in its development, homeostasis and response to damage and infection. Although microglia have been increasingly implicated in contributing to the pathology that underpins neurological dysfunction and disease, they also have crucial roles in neurological homeostasis and regeneration. This includes regulation of the maintenance and regeneration of myelin, the membrane that surrounds neuronal axons, which is required for axonal health and function. Myelin is damaged with normal ageing and in several neurodegenerative diseases, such as multiple sclerosis and Alzheimer disease. Given the lack of approved therapies targeting myelin maintenance or regeneration, it is imperative to understand the mechanisms by which microglia support and restore myelin health to identify potential therapeutic approaches. However, the mechanisms by which microglia regulate myelin loss or integrity are still being uncovered. In this Review, we discuss recent work that reveals the changes in white matter with ageing and neurodegenerative disease, how this relates to microglia dynamics during myelin damage and regeneration, and factors that influence the regenerative functions of microglia.Microglia are increasingly implicated in the maintenance and regeneration of myelin, which is damaged with normal ageing and in several neurodegenerative diseases. This article reviews the mechanisms by which microglia support and restore myelin health and the factors that influence these crucial microglial functions.

As resident macrophages of the CNS, microglia are critical immune effectors of inflammatory lesions and associated neural dysfunctions. In multiple sclerosis (MS) and its animal models, chronic microglial inflammatory activity damages myelin and disrupts axonal and synaptic activity. In contrast to these detrimental effects, the potent phagocytic and tissue-remodelling capabilities of microglia support critical endogenous repair mechanisms. Although these opposing capabilities have long been appreciated, a precise understanding of their underlying molecular effectors is only beginning to emerge. Here, we review recent advances in our understanding of the roles of microglia in animal models of MS and demyelinating lesions and the mechanisms that underlie their damaging and repairing activities. We also discuss how the structured organization and regulation of the genome enables complex transcriptional heterogeneity within the microglial cell population at demyelinating lesions.Microglia are detected in active lesions in multiple sclerosis (MS) and research in animal models has suggested diverse roles for these cells in neural damage and repair. Gosselin and colleagues discuss the mechanisms through which microglia contribute to neuropathology and the molecular mechanisms that regulate their function in demyelinating conditions.

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction. The mechanisms regulating central nervous system remyelination efficiency are poorly understood. Here, the authors show that remyelination is driven by astrocytes supporting oligodendrocyte survival, regulated by the Nrf2 and cholesterol pathways.

Oligodendrocytes that survive demyelination can remyelinate, including in multiple sclerosis (MS), but how they do so is unclear. In this study, using zebrafish, we found that surviving oligodendrocytes make few new sheaths and frequently mistarget new myelin to neuronal cell bodies, a pathology we also found in MS. In contrast, oligodendrocytes generated after demyelination make abundant and correctly targeted sheaths, indicating that they likely also have a better regenerative potential in MS. Neely et al. investigated the regeneration of different oligodendrocytes after demyelination. They found that newly generated cells exhibit much more proficient remyelination than those that survive demyelination, with implications for MS.

Regeneration of myelin is a dynamic, yet enigmatic process. Dombrowski et al. uncover a central role for regulatory T (T reg ) cells in driving oligodendrocyte differentiation, in part via CCN3, a novel factor in T reg function and oligodendrocyte biology. This identifies T reg cells as key cellular players in efficient remyelination. Regeneration of CNS myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells. In multiple sclerosis, remyelination can fail despite abundant oligodendrocyte progenitor cells, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS in multiple sclerosis, yet little is known about T cell functions in remyelination. We report that regulatory T cells (T reg ) promote oligodendrocyte differentiation and (re)myelination. T reg -deficient mice exhibited substantially impaired remyelination and oligodendrocyte differentiation, which was rescued by adoptive transfer of T reg . In brain slice cultures, T reg accelerated developmental myelination and remyelination, even in the absence of overt inflammation. T reg directly promoted oligodendrocyte progenitor cell differentiation and myelination in vitro . We identified CCN3 as a T reg -derived mediator of oligodendrocyte differentiation and myelination in vitro . These findings reveal a new regenerative function of T reg in the CNS, distinct from immunomodulation. Although the cells were originally named 'T reg ' to reflect immunoregulatory roles, this also captures emerging, regenerative T reg functions.

Myelination of projection neurons by oligodendrocytes is key to optimize action potential conduction over long distances. However, a large fraction of myelin enwraps the axons of parvalbumin-positive fast-spiking interneurons (FSI), exclusively involved in local cortical circuits. Whether FSI myelination contributes to the fine‐tuning of intracortical networks is unknown. Here we demonstrate that FSI myelination is required for the establishment and maintenance of the powerful FSI-mediated feedforward inhibition of cortical sensory circuits. The disruption of GABAergic synaptic signaling of oligodendrocyte precursor cells prior to myelination onset resulted in severe FSI myelination defects characterized by longer internodes and nodes, aberrant myelination of branch points and proximal axon malformation. Consequently, high-frequency FSI discharges as well as FSI-dependent postsynaptic latencies and strengths of excitatory neurons were reduced. These dysfunctions generated a strong excitation-inhibition imbalance that correlated with whisker-dependent texture discrimination impairments. FSI myelination is therefore critical for the function of mature cortical inhibitory circuits. Myelination optimizes conduction speed of excitatory neurons. However, whether myelination of interneurons (INs) refines cortical networks is unclear. Here, the authors show that INs myelination shapes feedforward inhibition of mouse cortical sensory circuits and impacts whisker-mediated behaviour.

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.Lloyd et al. find that regeneration of CNS myelin requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state, revealing new therapeutic targets for neurodegenerative disease.

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS. Single-cell RNA-seq of a mouse model of multiple sclerosis uncovers new oligodendrocyte populations and putative disease markers and suggests new mechanisms underlying the pathogenesis of the disease.

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination. In multiple sclerosis (MS), antigen-presenting cells inducing cytotoxic T cell response against mature oligodendrocytes remain to be identified. Here the authors show that oligodendrocyte precursors cross-present antigen taken up from mature oligodendrocytes, and are targeted by cytotoxic T cells in cell culture and in an animal model of MS.

The clearance of damaged myelin sheaths is critical to ensure functional recovery from neural injury. Here we show a previously unidentified role for microvessels and their lining endothelial cells in engulfing myelin debris in spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). We demonstrate that IgG opsonization of myelin debris is required for its effective engulfment by endothelial cells and that the autophagy–lysosome pathway is crucial for degradation of engulfed myelin debris. We further show that endothelial cells exert critical functions beyond myelin clearance to promote progression of demyelination disorders by regulating macrophage infiltration, pathologic angiogenesis and fibrosis in both SCI and EAE. Unexpectedly, myelin debris engulfment induces endothelial-to-mesenchymal transition, a process that confers upon endothelial cells the ability to stimulate the endothelial-derived production of fibrotic components. Overall, our study demonstrates that the processing of myelin debris through the autophagy–lysosome pathway promotes inflammation and angiogenesis and may contribute to fibrotic scar formation.Blood vessels help macrophage entry. Zhou et al. show that activated microvessels serve as critical portals for macrophage entry to boost inflammation after spinal cord injury.