187 White matter microglia heterogeneity reported in the cuprizone-mediated demyelination mouse model, which induces oxidative damage and mitochondrial dysfunction with selective damage to oligodendrocytes61, where microglia showed long lasting gene changes after cuprizone had been removed from the diet when remyelination proceeds. Signatures associated with both de- and remyelination revealed enriched expression of Apoe, Axl, Igf, Lyz2 and reduced Tmem119 expression61. Microglia states that were more enriched during demyelination or remyelination were in part recapitulated in biopsied MS lesions61. Recently, DAM-like signatures were identified in MS white matter lesions90,91. Additionally, two clusters of microglia were identified, one associated with myelin phagocytosis and clearance, while the other showed enrichment in iron related genes, antigen presentation and complement C1-complex genes90. Microglia are the primary source of C1q in the CNS92,93, and a conditional knockout of C1q in microglia resulted in reduced microglial activity after EAE induction90. Unlike comparative studies on microglia isolated from EAE and cuprizone models, human microglia studies revealed a greater microglia diversity in which gene expression only partially overlaps with mouse data75, likely reflecting species differences. However, this may also be due to differing age, regional variations or comorbidities. Studies on MS post-mortem tissues assessing single microglia transcriptomes identified several microglia clusters, reflecting the wide variation in microglia and macrophage profiles in MS lesions18,89. One must consider, however, that profiles of isolated microglia may also be influenced by cause of death, disease activity or stage, post-mortem interval, age or cell isolation protocols. Pathology studies reveal that macrophages and microglia in MS lesions were not solely pro- or anti-inflammatory, but rather demonstrated an intermediate profile15,94. Additionally, microglia in the white matter of MS showed a gene signature associated with increased lipid metabolism, while grey matter microglia had enriched expression of genes associated with glycolysis and iron homeostasis57. Furthermore, microglia in white matter MS lesions had significantly reduced expression of P2RY12 and TMEM119, while grey matter microglia did not95. However, TMEM119 was seen to be expressed in preactive MS lesions (that lack evidence of BBB disruption and T cells), and early active lesions, while macrophages were found to dominate developed lesions18,96. Likewise, in EAE, microglia activation preceded clinical disease in the CNS97 and depletion or inactivation of microglia and macrophages delayed disease onset and decreased clinical disease98. Changes in microglia states have also been observed in a mouse model of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a chronic immune-mediated inflammatory disease of the CNS characterised by optic neuritis and transverse myelitis99 caused by loss of AQP4 and GFAP due to the presence of autoantibodies targeting AQP4. While microglia in NMOSD showed enriched expression of genes associated with innate immune responses compared to controls, CD11c- microglia had enriched expression of genes related to mitosis, while CD11c+ microglia had enriched genes related to migration and antigen presentation100. Microglia in inflammatory white matter diseases, and those associated with demyelination and remyelination, show similarities in gene enrichment profiles. However, as these microglia states also have distinct enough signatures to distinguish them, it appears that microglia may have context-dependent transcriptomes and function.
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