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Roles and regulation of microglia activity in multiple sclerosis: insights from animal models

Abstract

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.

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Fig. 1: Microglial functions in the CNS.
Fig. 2: Microglial functions mediating damage in demyelinating disorders.
Fig. 3: Microglial functions contributing to myelin repair.
Fig. 4: Molecular regulators of microglial activity in demyelinating disorders.
Fig. 5: Mechanisms of microglial response coordination by distal cis-regulatory genomic elements.

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Acknowledgements

The authors thank A. Boisvert for assistance with manuscript editing, and M. Toghi for assistance with preparation of figures. F.D.-G. is supported by a Doctoral award from the Canadian Institutes of Health Research (CIHR). This work was supported by grants awarded to D.G. from the Scottish Rite Charitable Foundation of Canada, Multiple Sclerosis Society of Canada, Alzheimer’s Society of Canada and CIHR.

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Glossary

Antigen presentation

A process whereby antigens bound to a cell’s major histocompatibility complex (MHC) class I or II surface receptors are presented, respectively, to CD8 or CD4 lymphocytes to induce their activation.

Chemokines

Soluble proteins that mediate recruitment of cells through chemotaxis.

Cis-regulatory elements

(CREs). Genomic regulatory elements that encompass binding sites for transcription factors implicated in the regulation of associated genes.

Complement pathway

A coordinated protein cascade involved in immune defence; also increasingly involved in mediating essential functions in the development and maintenance of neuronal circuitries.

Cytokine

A soluble protein that mediates cell-to-cell communication.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules typically released by injured cells that are endowed with the ability to trigger potent inflammatory responses.

Demyelinating lesions

Lesions of the nervous system characterized by damage and/or loss of myelin on axons.

Endolysosomal system

A system of cell biology that mediates trafficking, recycling and/or disposal through proteolysis of molecular cargo contained within membranous organelles.

Gene promoters

Genomic regulatory elements that encompass transcriptional start sites of protein-coding genes along with binding sites for transcription factors involved in the recruitment and positioning of the RNA polymerase II transcriptional complex.

Genetic susceptibility variants

Genetic alterations that increase risk for the development of a disease or disorder.

Inflammasome

A protein complex that cleaves the pro-form of interleukin-1β (IL-1B) and other IL-1 family members to produce their mature, signalling forms.

Lipofuscin

Granules, largely composed of lipid remains, that may form and persist over time in lysosomes under certain circumstances.

Multiplexed protein imaging

Techniques that enable the detection and quantification of multiple target proteins in parallel, or serially, in situ.

Opsonization

A process whereby proteins bind and coat targeted structures to enable and/or facilitate their disposal.

Phagocytosis

A form of endocytosis involved in the internalization of particles larger than 0.5 μm in diameter.

Reactive oxygen species

(ROS). Highly reactive chemicals produced through the partial reduction of oxygen.

Scavenger receptors

A diverse group of cell surface receptors that mediate endocytosis of a wide variety of particles, including lipids, carbohydrates and apoptotic cells.

Single-cell RNA sequencing

A gene profiling technique that allows the comprehensive assessment of relative gene expression at the single-cell level.

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Distéfano-Gagné, F., Bitarafan, S., Lacroix, S. et al. Roles and regulation of microglia activity in multiple sclerosis: insights from animal models. Nat Rev Neurosci 24, 397–415 (2023). https://doi.org/10.1038/s41583-023-00709-6

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