Microglia Diversity in Health and Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a neurodegenerative disease characterized by multiple focal lesions, ongoing demyelination and, for most people, a lack of remyelination. MS lesions are enriched with monocyte-derived macrophages and brain-resident microglia that, together, are likely responsible for much of the immune-mediated neurotoxicity. However, microglia and macrophage also have documented neuroprotective and regenerative roles, suggesting a potential diversity in their functions. Linked with microglial functional diversity, they take on diverse phenotypes developmentally, regionally and across disease conditions. Advances in technologies such as single-cell RNA sequencing and mass cytometry of immune cells has led to dramatic developments in understanding the phenotypic changes of microglia and macrophages. This review highlights the origins of microglia, their heterogeneity throughout normal ageing and their contribution to pathology and repair, with a specific focus on autoimmunity and MS. As phenotype dictates function, the emerging heterogeneity of microglia and macrophage populations in MS offers new insights into the potential immune mechanisms that result in inflammation and regeneration.

Keywords: ageing; macrophages; microglia; multiple sclerosis; remyelination; single-cell RNA sequencing; single-cell analysis.

Figure 1

Overlap of upregulated genes between early postnatal microglia and microglia in diseased models. Subsets of early postnatal microglia (ATMs, PAMs, Cd11c+) with similar transcriptomic profiles were observed in three independent studies (53, 54, 58). The transcriptomic profile of an Alzheimer’s model (DAMs) (64) and an acute demyelination model (8) also show overlap with these postnatal microglia. The top ten upregulated genes from each dataset are shown with three genes that are common to all five datasets (Spp1, Igf1, Lyz2).

Figure 2

Changing microglia heterogeneity throughout development. Peak microglial heterogeneity is seen during embryonic development, with a decrease in adulthood, and a subsequent increase in the aged brain (65). Enriched genes and phenotypes significant to each microglial developmental stage are shown, with genes that are unique to each stage in blue. Hammond et al. reported a subset of embryonic microglia uniquely expressing Ms4a7, suggesting a similarity to BAMs.

Figure 3

Regional differences in microglial phenotypes in the mouse brain. Regions showing similar microglial phenotypes are similarly coloured (cortex and striatum = blue, cerebellum and hippocampus = yellow). Phenotypic characteristics and signature genes for each region are shown.

Figure 4

Factors contributing to microglial heterogeneity in MS lesions. A variety of factors likely contribute to the diversity of the microglial phenotype in MS. These include: 1) temporal lesion evolution, 2) ongoing neurodegeneration and 3) remyelination/demyelination in the surrounding environment, 4) location within the lesion and 5) anatomical location within the brain.