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Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease

Nature Reviews Neuroscience volume 15, pages 300–312 (2014)Cite this article

Subjects

Key Points

  • Microglia are a unique lineage of tissue macrophages that are distinct from any other type of myeloid cell inside and outside the brain. They originate exclusively from erythromyeloid precursors in the yolk sac. Microglia are long-lived and self-renew to ensure cell expansion.

  • Microglia can be distinguished from other myeloid cells in the brain by characteristic gene expression profiles. The molecules CSF1R (colony-stimulating factor 1 receptor), DAP12 (DNAX-activation protein 12), IRF8 (interferon regulatory factor 8) and transcription factor PU.1 are essential for the development and activity of microglia.

  • Microglia are vital for normal brain function and sensitive to degeneration. Microglial dysfunction can cause neuropsychiatric diseases that we have named microgliopathies.

  • Therapeutic benefit in neurological and psychiatric disorders can come from targeting bone marrow-derived myeloid cells to the CNS. Preclinical evidence is provided in animal models of Alzheimer's disease and Rett syndrome.

  • Innate immune cells in the CNS (microglia, monocytes, macrophages and dendritic cells) show complex interactions in response to pathogens, tissue damage and lymphocyte interactions, and reprogramme their function in an adaptive process termed polarization.

Abstract

Mononuclear phagocytic cells in the CNS used to be defined according to their anatomical location and surface marker expression. Recently, this concept has been challenged by the results of developmental and gene expression profiling studies that have used novel molecular biological tools to unravel the origin of microglia and to define their role as specialized tissue macrophages with long lifespans. Here, we describe how these results have redefined microglia and helped us to understand how different myeloid cell populations operate in the CNS based on their cell-specific gene expression signatures, distinct ontogeny and differential functions. Moreover, we describe the vulnerability of microglia to dysfunction and propose that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.

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Figure 1: Myeloid cell types in the CNS.
Figure 2: Embryonic and postnatal development of microglia in mice.
Figure 3: Development of resident macrophages in different tissues.
Figure 4: Functional reprogramming of microglia and macrophages in response to brain injury.
Figure 5: Disease-modulating roles of bone marrow-derived myeloid cells in the CNS.

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Acknowledgements

The authors apologize to all of those colleagues whose work was discussed without proper quotation owing space constraints. The authors thank S. M. Brendecke for critically reading the manuscript and M. Knust for help with the artwork. M.P. and J.P. are joint coordinators of the DFG-funded research unit (FOR) 1336. In addition, M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Gemeinnützige Hertie-Stiftung (GHST), the Fritz Thyssen Stiftung, the competence network of neurodegenerative disorders (KNDD) and the DFG (SFB 992). J.P. receives additional funding from the DFG (SFB/TRR43 and the Cluster of Excellence NeuroCure), the BMBF (Forschungsnetz zu psychischen Erkrankungen) and the Berlin Institute of Health.

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Authors and Affiliations

  1. Institute of Neuropathology, University of Freiburg, Breisacherstraße 64, Freiburg, 79106, Germany

    Marco Prinz

  2. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, 79104, Germany

    Marco Prinz

  3. Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Josef Priller

  4. Cluster of Excellence NeuroCure, Charitéplatz 1, Berlin, 10117, Germany

    Josef Priller

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  1. Marco Prinz
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PowerPoint slides

Glossary

Macrophages

Tissue-resident cells of the mononuclear phagocyte system that are characterized by their ability to phagocytose foreign particulate material, debris and colloidal material.

Mononuclear phagocytes

A mononuclear cell type of the myeloid lineage (macrophages, monocytes or dendritic cells) that have the ability to phagocytose.

Dendritic cells

Also known as an interdigitating reticular cells because of their branched morphology. Dendritic cells are the most potent stimulators of T cell responses.

Monocyte

A type of mononuclear leukocyte that is derived from the bone marrow and circulates in the bloodstream. Monocytes typically migrate into tissues, where they can differentiate into various types of macrophages.

Haematopoietic stem cells

(HSCs). Rare multipotent cells that give rise to all blood cells, including myeloid and lymphoid lineages.

Leukocytes

White blood cells derived from multipotent haematopoietic stem cells in the bone marrow. Leukocytes are of myeloid or lymphoid lineage and are found in the blood and lymphatic system.

Yolk sac

A membranous sac attached to the embryo that provides early nourishment in the form of yolk. It functions as the developmental circulatory system of the embryo before internal circulation begins.

CD45

(Also known as leukocyte common antigen and PTPRC). A type I transmembrane protein present on all haematopoietic cells that assists in cell activation and the levels of which are reduced in mature parenchymal microglia.

Neuroepithelium

The ectodermal epithelium in the embryo from which the CNS and its main cellular constituents (neurons, astrocytes, oligodendrocytes and ependymal cells) are derived.

Natural killer cells

A type of cytotoxic lymphocyte that are crucial for the innate immune system.

Myelopoiesis

The regulated formation of myeloid cells, including macrophages, monocytes, dendritic cells and granulocytes. Myelopoiesis takes place in the bone marrow or the yolk sac.

Deep RNA sequencing

An approach enabled by next-generation sequencing technology that is particularly useful for identifying low-abundance RNAs or low-frequency mutations.

Parabiotic mice

Mice in which shared blood circulation is created via surgical intervention. This procedure enables the fate of labelled donor cells to be followed in the parabiotic partner.

Graft-versus-host disease

A complication following an allogeneic tissue transplant in which immune cells (white blood cells) in the tissue (the graft) recognize the recipient (the host) as 'foreign'.

X-linked adrenoleukodystrophy

A rare X chromosome-linked disorder resulting from mutations in ABCD1 (ATP-binding cassette subfamily D member 1) that cause defects in peroxisomal β-oxidation and lead to the accumulation of very-long-chain fatty acids, particularly in the CNS and adrenal cortex.

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Prinz, M., Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15, 300–312 (2014). https://doi.org/10.1038/nrn3722

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