Microglial subtypes: diversity within the microglial community

Abstract

Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination

“…The expression data showed that several genes from the category "regulation of MAPK cascade" were differentially regulated in both Csf1-/-and wild type mice ( Figure 5B,C). Many of the genes within this category (Apoe, Csf1R, Ccl7, Ccl2, Tlr6, Tlr13, Ccl9, Ccl3, and Clec7a) are known to be developmentally and/or pathologically-regulated in microglia [54][55][56][57] and, as expected, were significantly less upregulated after demyelination in Csf1-/-than in wild types. Interestingly, within this category, we identified a group of genes significantly upregulated (p < 0.05) in Csf1-/-mice.…”

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

“…Recently, deep single-cell RNA sequencing (scRNAseq) data from isolated microglia cells has revealed several transcriptionally distinct clusters throughout each developmental stage [170][171][172]. Based on this evidence, Stratoulias and colleagues (2019) hypothesized that microglia constitute a heterogeneous population, in which each cell displays intrinsic properties and functional specializations regardless of the structure [173]. As a result, neighboring microglial cells may have different responses to the same stimulus.…”

Commentary: Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

“…Moreover, so-called M1 and M2 gene signatures often coexist in complex mixed phenotypes; the dichotomous paradigm is not supported by transcriptional profiling of human macrophages or monocytes activated by diverse ligands (22). Emerging evidence suggests that microglial subtype categorization should consider both their environmentdependent plasticity and subtypes with inherent functional specificity (23). Technologies that can assist in these efforts include two-photon imaging, whole-genome transcriptomic and epigenomic analyses at the cellular level, mass cytometry, and high-content experimental models (19).…”