183 White matter microglia heterogeneity Disease Associated Microglia (DAMs) Spp1 Apoe Lpl P2ry12 Tmem119 Cx3cr1 White matter Associated Microglia (WAMs)Apoe Cd63 Clec7a P2ry12 Tmem119 Cx3cr1 Csf1r Proliferative region Associated Microglia (PAMs) Clec7a Spp1 Gpnmb Igf1 P2ry12 Tmem119 Cx3cr1 Demyelination Associated Microglia Fam20c Apoe Ccl6 Spp1 Tmem119 MS Associated Microglia APOE FAM20C DAB2 MAFB P2RY12 TMEM119 CX3CR1 SLC2A5 Remyelination Associated Microglia Apoe Cybb Cd74 Tmem119 EAE Associated Microglia Ccl2 Cxcl10 Ly86 Mki67 P2ry12 Tmem119 Selplg Slc2a5 DAMG2 DAMG3 DAMG4 Cd74 Ctsb Apoe Cxcl10 Tnf Ccl4 Ccl5 Ctss Imt2b Cuprizone Figure 3. Microglia states in development and disease. Multiple microglia states have been identified in mice throughout development, ageing and disease, some of which have partially overlapping signatures. Similarly, microglia expression profiles in mouse models of MS, cuprizone and experimental autoimmune encephalomyelitis (EAE), only partially overlap with that of MS-associated microglia, likely reflecting species differences Additionally, white matter microglia have higher elasticity and viscosity, compared to grey matter microglia59, which might impact microglial ability to phagocytose60. A subset of macrophages has also been identified lining the apical surface of the choroid plexus epithelium, also known as Kolmer’s epiplexus cells. These epiplexus macrophages share microglial signature genes such as Sall1 and have a transcriptional signature reminiscent of ‘damage/disease-associated microglia’ (DAM) under homeostatic conditions, suggesting possible roles in responses to pathology24. Overall, white matter microglia appear to have properties and engage pathways involved in inflammation, more so than those in the grey matter (Table 1). Microglia heterogeneity in development and ageing Development Regional and temporal heterogeneity of microglia are observed during development46,61-63. Developmental white matter microglia exhibit a more activated profile compared to those in the cortex, as defined by expression of genes associated with activated microglia including Spp1, Itgax, Gpnmb, Igf1 and Clec7a64. Regional heterogeneity is further indicated by the more pronounced depletion of white matter microglia in mice deficient in the CSF1R ligand CSF-1, particularly in the spinal cord65,66. Indeed, differential expression of Csf-1 and IL-34 between the white and grey matter has recently been shown, with white matter microglia depending more on Csf-1 for their development/maintenance potentially explaining this heterogeneity66. Single-cell sequencing studies have characterised the heterogeneity of
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