Microglia and macrophages in brain homeostasis and disease

Key Points

  • Microglia arise solely from yolk sac erythromyeloid precursors under normal conditions, although the precise nature of these precursors is controversial.

  • Peripheral cells can infiltrate the central nervous system (CNS) in certain artificial or pathological conditions, but the functional significance of different microglial origins remains elusive.

  • Microglial precursors migrate to the brain parenchyma and quickly diverge from other tissue-resident macrophages, in terms of their gene expression profile, under the influence of unknown brain-derived signals.

  • During homeostasis, microglia maintain steady, region-specific densities by self-renewal.

  • Microglia interact with almost all CNS components during embryonic and postnatal development, when they carry out a large number of non-immune tasks that are crucial for brain function.

  • Microglia have multidimensional activation states in CNS diseases and injuries, such that these cells can have beneficial or detrimental roles depending on the context.

Abstract

Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.

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Figure 1: The microenvironments and genetic signatures for brain macrophages.
Figure 2: Ontogeny and development of microglia and tissue macrophages.
Figure 3: Microglial functions in development and homeostasis.
Figure 4: Microglial functions during CNS injuries and diseases.

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Acknowledgements

The authors thank members of the Barres laboratory for providing valuable feedback, especially C. J. Bohlen, M.-M. Fu, F. C. Bennett, M. L. Bennett and L. Zhou. Q.L. is supported by the Jeffry M. and Barbara Picower (JPB) foundation and Stanford University School of Medicine Dean's Postdoctoral Fellowship.

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Q.L. was responsible for researching, writing and editing the manuscript. B.A.B. contributed to reviewing and editing the manuscript before submission.

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Correspondence to Qingyun Li or Ben A. Barres.

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B.A.B. is a co-founder of Annexon Biosciences, Inc., a company that is making drugs for neurological diseases. Q.L. declares no conflict of interest.

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Glossary

Blood–brain barrier

(BBB). A physiological barrier between blood vessels and brain parenchyma. It is formed by specialized tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane and an additional membrane formed from astrocytic end feet, known as the glial basement membrane (glia limitans).

Basal ganglia

A group of interconnected nuclei (clusters of neurons) that lie deep beneath the cerebral cortex. They are responsible for modulating motor control, planning actions and executing habitual behaviours, as well as influencing cognition and emotion.

Parabiosis

An experimental model system in which two animals (most often mice) are surgically joined to establish a common circulation.

Epigenetic memory

Molecular mechanisms modifying DNA or chromosomal configuration without changing gene sequences that lead to stable changes in gene expression long after the disappearance of initial developmental or environmental signals.

Complement system

A signalling cascade that can be activated by any of three independent pathways. The classical pathway is activated by antigen–antibody immune complexes. The alternative pathway is triggered by direct hydrolysis of complement component C3. The lectin pathway is activated by the binding of lectin to mannose residues on the surface of pathogens.

Layer V neurons

Neurons in layer V of the six-layered mammalian neocortex. This layer contains excitatory neurons that project either to the contralateral hemisphere or to subcortical brain regions, such as the thalamus and brainstem.

Axon fasciculation

A neurodevelopmental process in which axons that travel in the same direction often adhere together to form a tight bundle.

Corpus callosum

A thick bundle of nerve fibres that connect the left and right hemispheres of the brain and form the most prominent white-matter structure.

Tauopathy

A member of a class of neurodegenerative disorders that are manifested by intracellular accumulation of hyperphosphorylated microtubule-associated protein tau. These insoluble protein aggregates form neurofibrillary tangles and often underlie the pathological conditions of dementia and Parkinson disease.

Nodes of Ranvier

Periodic axonal segments, rich in ion channels, that are not covered by myelin sheaths; this allows rapid propagation of an action potential from one node of Ranvier to the next along the fibre.

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Li, Q., Barres, B. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18, 225–242 (2018). https://doi.org/10.1038/nri.2017.125

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