Abstract
Gene expression analyses of microglia, the tissue-resident macrophages of the central nervous system (CNS), led to the identification of homeostatic as well as neurological disease-specific gene signatures of microglial phenotypes. Upon alterations in the neural microenvironment, either caused by local insults from within the CNS (during neurodegenerative diseases) or by macroenvironmental incidents, such as social stress, microglia can switch phenotypes—generally referred to as “microglial activation.” The interplay between the microenvironment and its influence on microglial phenotypes, regulated by (epi)genetic mechanisms, can be imagined as the different colorful crystal formations (microglial phenotypes) that change upon rotation (microenvironmental changes) of a kaleidoscope. In this review, we will discuss microglial phenotypes in relation to neurodevelopment, homeostasis, in vitro conditions, aging, and neurodegenerative diseases based on transcriptome studies. By overlaying these disease-specific microglial signatures, recent publications have identified a specific set of genes that is differentially expressed in all investigated diseases, called a microglial core gene signature with multiple diseases. We will conclude this review with a discussion about the complexity of this microglial core gene signature associated with multiple diseases.
Highlights
Macrophages are innate immune cells that reside in all organs of the body
Concluding, the central nervous system (CNS) is populated by different macrophage cell types, and even microglia in the parenchyma can be subdivided into different phenotypes based on their gene expression profiles, which might be associated with specific functions
The comparison between cultured microglia with ex vivo microglia has not been performed, the current results suggest that in vitro microglia lose many genes belonging to the homeostatic gene signature, though microglia can still be segregated from other brain cells in single-cell sequencing analysis (66)
Summary
Macrophages are innate immune cells that reside in all organs of the body. They have versatile functions that are tailored to the organ of residence (1). The common denominator of at least these seven studies is the identification of the homeostatic microglial signature genes, including Sall[1], Hexb, Fcrls, Gpr[43], Cx3cr[1], Tmem[119], Trem[2], P2ry[12], Mertk, Pros[1], and SiglecH, that are uniquely/higher expressed in microglia and not or only at low levels in other brain cells or myeloid cell types, including tissue-resident macrophage subsets and monocytes.
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