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

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'. Access through your

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BEING VIEWED BY OTHERS BRAIN MACROPHAGE DEVELOPMENT, DIVERSITY AND DYSREGULATION IN HEALTH AND DISEASE Article Open access 26 June 2023 ARG1-EXPRESSING MICROGLIA SHOW A DISTINCT MOLECULAR

SIGNATURE AND MODULATE POSTNATAL DEVELOPMENT AND FUNCTION OF THE MOUSE BRAIN Article Open access 11 May 2023 MONOCYTE-DERIVED MACROPHAGES ACT AS REINFORCEMENTS WHEN MICROGLIA FALL SHORT IN

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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. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Institute of Neuropathology, University of Freiburg, Breisacherstraße 64, Freiburg, 79106, Germany Marco Prinz * BIOSS Centre for Biological Signalling Studies, University of

Freiburg, Freiburg, 79104, Germany Marco Prinz * Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117,

Germany Josef Priller * Cluster of Excellence NeuroCure, Charitéplatz 1, Berlin, 10117, Germany Josef Priller Authors * Marco Prinz View author publications You can also search for this

author inPubMed Google Scholar * Josef Priller View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Marco Prinz or

Josef Priller. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2

POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 POWERPOINT SLIDE FOR TABLE 1 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. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 09 April 2014 * Issue Date: May 2014 * DOI: https://doi.org/10.1038/nrn3722

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