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Review
. 2018 Jun;78(6):561-579.
doi: 10.1002/dneu.22545. Epub 2017 Oct 24.

Development and maintenance of the brain's immune toolkit: Microglia and non-parenchymal brain macrophages

Jose P Lopez-Atalaya  1 , Katharine E Askew  2 , Amanda Sierra  3   4   5 , Diego Gomez-Nicola  2
Affiliations
Review

Development and maintenance of the brain's immune toolkit: Microglia and non-parenchymal brain macrophages

Jose P Lopez-Atalaya et al. Dev Neurobiol. 2018 Jun.

Abstract

Microglia and non-parenchymal macrophages located in the perivascular space, the meninges and the choroid plexus are independent immune populations that play vital roles in brain development, homeostasis, and tissue healing. Resident macrophages account for a significant proportion of cells in the brain and their density remains stable throughout the lifespan thanks to constant turnover. Microglia develop from yolk sac progenitors, later evolving through intermediate progenitors in a fine-tuned process in which intrinsic factors and external stimuli combine to progressively sculpt their cell type-specific transcriptional profiles. Recent evidence demonstrates that non-parenchymal macrophages are also generated during early embryonic development. In recent years, the development of powerful fate mapping approaches combined with novel genomic and transcriptomic methodologies have greatly expanded our understanding of how brain macrophages develop and acquire specialized functions, and how cell population dynamics are regulated. Here, we review the transcription factors, epigenetic remodeling, and signaling pathways orchestrating the embryonic development of microglia and non-parenchymal macrophages. Next, we describe the dynamics of the macrophage populations of the brain and discuss the role of progenitor cells, to gain a better understanding of their functions in the healthy and diseased brain. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 561-579, 2018.

Keywords: development; lineage; microglia; progenitor; self-renewal.

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Figures

Figure 1
Figure 1
Diversity of myeloid cell types in the adult CNS. The CNS is filled with a variety of resident innate immune cells that regulate homeostasis and execute surveillance tasks. Microglia cells tile the entire brain in a contiguous and essentially non‐overlapping manner that is orderly and well organized to actively screen the brain parenchyma for incoming threats. Three other major types of brain‐resident macrophages are present in the outer boundaries of the brain, such as the perivascular space, choroid plexus, and in the meninges where it is thought they constitute the first line of host defense against cellular or pathogenic components. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 2
Figure 2
From EMP to microglia. Microglia arise early during development from EMP in the embryonic yolk sac that seed the mouse brain rudiment around E9.0 upon commitment to immature macrophage cells showing ameboid morphology and a high proliferation rate (also known as A cells; Bertrand et al., 2005). Amoeboid cells persist during the first 2 weeks of the postnatal brain where they gradually acquire the ramified shape characteristic of the active microglia in the steady state. Commitment of EMP through immature ameboid macrophages, towards differentiate microglia is regulated by intrinsic genetic programs and environmental signals. Initially, a small subset of master regulators of macrophage development, including, PU.1, C/EBPs, RUNX1, and IRF8, cooperatively drives specification and fate acquisition of EMPs into immature macrophages. In the brain, environmental factors such as CSF1, IL34, and TGFβ play fundamental roles in shaping, maintaining, and reinforcing microglial identity. Recent genome‐wide analyses have identified several transcription factors that are specific or highly enriched in microglia. These include SALL1, SALL3, MEIS3, and MAFB. However, their roles in microglia biology remain to be elucidated. To date, SALL1 have been shown to maintain microglia identity and to regulate phenotypic plasticity. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 3
Figure 3
Cell cycle and proliferation rates of microglia. (A) Calculations of microglial turnover estimate a cell cycle length of approximately 32 h with S phase lasting approximately 16 h (Askew et al., 2017). (B) In the adult brain, the microglial population is maintained by self‐renewal of resident cells with no contribution from peripheral bone marrow‐derived cells. There is a tight temporal and spatial coupling between proliferation and apoptosis in order to maintain a stable cell density throughout lifetime, leading to a constant reorganization of the microglial landscape. (C) Comparison of the microglial proliferation rate (%) 24 h post‐labelling from studies in mice (blue) by Lawson et al. (1992), Babcock et al., (2013), Askew et al. (2017), Tay et al. (2017), and in human (red) by Reu et al. (2017). Note Lawson et al. used 3H‐thymidine and estimated a 0.05% proliferation rate by analyzing 2 h after dosing, instead of the 24 h shown here. Askew et al. used a single dose of BrdU in 24 h, whilst Tay et al. used cumulative BrdU (1 dose/d) and Babcock et al., used three doses of BrdU in 24 h (therefore allowing labeling of 1–2 S phases). Reu et al. used IdU and 14C. [Color figure can be viewed at http://wileyonlinelibrary.com]
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