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Review
. 2015 May;138(Pt 5):1138-59.
doi: 10.1093/brain/awv066. Epub 2015 Mar 29.

Roles of microglia in brain development, tissue maintenance and repair

Mackenzie A Michell-Robinson  1 , Hanane Touil  1 , Luke M Healy  1 , David R Owen  2 , Bryce A Durafourt  1 , Amit Bar-Or  1 , Jack P Antel  1 , Craig S Moore  3
Affiliations
Review

Roles of microglia in brain development, tissue maintenance and repair

Mackenzie A Michell-Robinson et al. Brain. 2015 May.

Abstract

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease.

Keywords: brain development; inflammation; microRNA; microglia; neurodegeneration; neuroimmunology.

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Figures

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The number of functions ascribed to microglia has increased greatly in recent years. Michell-Robinson et al. review the roles of microglia in health and disease, in particular their contributions to brain development and tissue maintenance, and discuss the potential of targeting microglia to enhance brain repair.
Figure 1
Figure 1
Primitive and definitive haematopoietic contributions to specific tissue macrophage populations. Some tissue macrophages such as microglia are derived from yolk sac erythromyeloid progenitors during primitive haematopoiesis in early embryonic development. In some cases (e.g. Langerhans cells), foetal progenitors within the liver can also contribute to tissue macrophage populations. Tissue macrophage populations are maintained in the adult organism by local self-renewal and/or monocytes recruited from the periphery. In some cases (e.g. microglia) local self-renewal is the only method by which maintenance occurs. Middle: The contribution of peripheral myeloid cells to the maintenance of specific tissue macrophage populations is tissue-dependent. Here, it is shown as a list with peripheral contribution to specific tissue macrophage populations increasing from left to right. Near the end of the list, populations of tissue macrophages that are completely maintained by peripheral monocytes are shown (e.g. intestinal macrophages and dermal macrophages). Some types, such as white pulp macrophages (spleen), adipose-associated macrophages, and interstitial macrophages (lung) have an undetermined maintenance mechanism and are not depicted (Sieweke and Allen, 2013; Haldar and Murphy, 2014). Pleural macrophages (lung) and peritoneal macrophages each have two distinct subpopulations: a large majority, which originates from the yolk sac is self-maintained, while a smaller group is maintained by monocytes from the periphery (Haldar and Murphy, 2014). The general mechanisms of primitive and definitive haematopoiesis are shown. Tissue-resident macrophages, such as foetal and adult haematopoietic stem cells (HSC), undergo low rates of homeostatic proliferation to self-maintain their populations (represented by green arrows), and may undergo high rates of proliferation when challenged (injury, infection, irradiation, etc. represented by red arrows) (Sieweke and Allen, 2013). Black arrows represent the transient amplification of granulocyte-macrophage (GMP) and macrophage-dendritic progenitors (MDP) during normal haematopoiesis. Overall the majority of these findings come from experiments performed in rodents.
Figure 2
Figure 2
Pro-inflammatory ‘M1’ and quiescent/anti-inflammatory ‘M2’ microglia are regulated by the cytokine milieu. Both M1 and M2 microglia phenotypes have several purported roles in the injured CNS, including phagocytosing potential antigens, clearing cell debris, activating cells of the adaptive immune system, and directly contributing to mechanisms related to both neurodegeneration and repair. In response to pro-inflammatory stimuli [e.g. GM-CSF (CSF2), LPS, IFNγ], several cell surface molecules and soluble mediators are upregulated. In the CNS (e.g. CD80, CD86, CCR7), release of TNF and IL6 from microglia can lead to the activation of astrocytes, which in turn can support a permissive microenvironment that harnesses T and B cell recruitment and survival. CSF1 alone or in combination with IL4 and IL13 maintains a quiescent, anti-inflammatory, and/or tissue regenerative phenotype (often termed M2). These cells can express several different Fc receptors (e.g. CD23), C-type lectin molecules (e.g. CD206 and CD209), and release cytokines TGFβ1, IL10 and IL13. In the brain, microglia can also maintain a homeostatic and/or quiescent state by interacting with ligands (e.g. CX3CL1, CD47, CSF1 and CD200) on the surfaces of other neural cells, such as astrocytes and neurons. Asterisk represents quiescence markers and soluble factors not yet validated in human microglia.
Figure 3
Figure 3
Functional properties of microglia in the normal and aged brain. Ageing has been demonstrated to significantly impact the functionality of microglia. Age-associated changes in motility, proliferation, phagocytosis, and gene expression profiles of microglia are thought to be, in part, as a consequence of cumulative activation in response to systemic infections over time. These changes can lead to a complete loss of function, but also dysfunction and even hyper-reactive responses in aged microglia, thus reducing these cells capacity to effectively survey the CNS environment, maintain homeostasis, and respond both rapidly and efficiently to injury and disease.
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