REVIEWS Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease Marco Prinz1,2 and Josef Priller3,4 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’. macrophages Macrophages Microglia are tissue-resident in the CNS. distinguish them from their peripheral relatives have 9 Tissue-resident cells of the They belong to a group of mononuclear phagocytes that been identified . Moreover, recent fate-mapping stud- mononuclear phagocyte comprises peripheral tissue macrophages, CNS-associated ies of several macrophage populations in the body have system that are characterized macrophages, dendritic cells and monocyte-derived cells1,2. provided elegant evidence that, under homeostatic con- by their ability to phagocytose foreign particulate material, As such, they are critical effectors and regulators of ditions, microglia are not derived from the bone marrow 10–12 debris and colloidal material. changes in CNS homeostasis during development and in but originate from HSCs in the yolk sac . Thus, the health and disease. existing model of tissue macrophage development needs All mononuclear cells originate from haematopoietic to be extended to highlight the different origins of many 1Institute of Neuropathology, stem cells (HSCs) and develop along distinct differen- macrophage populations, including microglia. University of Freiburg, tiation pathways in response to endogenous and envi- Several other important distinctions between differ- Breisacherstraße 64, ronmental cues3,4. The body’s mononuclear phagocyte ent macrophage populations have been identified. Novel 79106 Freiburg, Germany. 2BIOSS Centre for Biological system was for a long time believed to derive from a myeloid-specific gene targeting techniques targeting Signalling Studies, subgroup of white blood cells called leukocytes that are CX3C chemokine receptor 1 (Cx3cr1; also known as the University of Freiburg, produced from HSCs. It was assumed that bone marrow- fractalkine receptor) have enabled researchers to examine 79104 Freiburg, Germany. 3 derived monocytes, a subgroup of leukocytes, circulate in the kinetics of myeloid cell turnover during homeostasis Department of 13–15 Neuropsychiatry and the blood and enter the tissues (where they differentiate and disease . These new transgenic approaches have Laboratory of Molecular into tissue-resident macrophages) in non-pathological helped to establish the major kinetic features of micro- Psychiatry, conditions and during inflammation. However, this view glia that distinguish them from other macrophages: Charité – Universitätsmedizin has changed in recent years as a result of the discovery namely, that they are long-lived, that they are not nor- Berlin, Charitéplatz 1, of new subtypes of mononuclear phagocytes that have mally replaced by peripheral cells from the circulation and 10117 Berlin, Germany. 5 4Cluster of Excellence different origins and distinct roles in CNS disorders . that they are able to self-renew in a context-dependent NeuroCure, Charitéplatz 1, Furthermore, the findings of recent population-based manner to ensure cell expansion. Previous studies used 10117 Berlin, Germany. gene expression studies have highlighted macrophage genes such as Cd11b (also known as Itgam), lysozyme M e‑mails: marco.prinz@ heterogeneity6–8. (Lysm; also known as Lyz2) and ionized calcium-binding uniklinik-freiburg.de; [email protected] Emerging evidence from such studies suggests that adaptor molecule 1 (Iba1; also known as Aif1) to target 16–18 doi:10.1038/nrn3722 microglia differ considerably from the macrophages myeloid cells in the brain . However, these experiments Published online 9 April 2014 that reside in other tissues6. Indeed, some genes that either used transgenic mouse lines that showed low levels NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS Mononuclear phagocytes of recombination in microglia compared with circulating myeloid- and macrophage-specific markers (such 13 A mononuclear cell type of the myeloid cells (such as in the Lysm-Cre line) or used the as IBA1, F4/80 (also known as EMR1) and CX3CR1 myeloid lineage (macrophages, antiviral drug ganciclovir, which has tremendous drug- (REF. 1)) and exhibit similar immune regulatory func- monocytes or dendritic cells) induced effects on microglia proliferation in vivo19. tions (such as local immune surveillance and removal that have the ability to phagocytose. Bone marrow-derived phagocytes often have dis- of debris), early results suggested that they have distinct ease-related functions that are distinct from those of ontogenesis22,23. Dendritic cells yolk sac-derived microglia1. The differential roles of The precise origin of microglia during brain develop- Also known as an microglia and other brain macrophages have tremen- ment has been a matter of controversy for decades. As interdigitating reticular cells dous clinical implications for the treatment of severe shown in FIG. 2, HSCs are the founders of the haemat- because of their branched morphology. Dendritic cells are brain diseases such as Alzheimer’s disease, Parkinson’s opoietic system, which is responsible for blood produc- the most potent stimulators of disease, amyotrophic lateral sclerosis (ALS; also known tion. Starting at embryonic day 10.5 (E10.5), they emerge T cell responses. as Lou Gehrig’s disease), multiple sclerosis and several from ventral aortic haematogenic endothelial cells in psychiatric disorders1,20,21. In theory, if practical hurdles the aorta–gonad–mesonephros (AGM) region of the Monocyte A type of mononuclear can be overcome, specific myeloid populations — such embryo. At E10.5, HSCs are only found in the embry- leukocyte that is derived from as phagocytes derived from the yolk sac, bone marrow or onic AGM region, and HSC expansion activity becomes the bone marrow and blood — might be used to deliver therapeutic molecules detectable24,25. HSC-derived myeloid cells are then pro- circulates in the bloodstream. to the CNS in order to ameliorate disease. duced abundantly in the fetal liver by E12.5. HSCs from Monocytes typically migrate In this Review, we provide an overview of the progress these two sources also develop into myeloid cells such as into tissues, where they can differentiate into various types in our understanding of the origin, fate and function of monocytes and potentially perivascular, choroid plexus of macrophages. microglia and compare this with other brain macrophage and meningeal macrophages. After birth, these types of populations. This information may help us to design new myeloid cell continue to be formed in the bone marrow Haematopoietic stem cells strategies to promote restoration of tissue homeostasis in from HSCs via myeloid precursors and macrophage and/ (HSCs). Rare multipotent cells that give rise to all blood cells, the most complex organ of the body, the brain. or dendritic cell progenitors. However, the precise lineage including myeloid and relationship between parenchymal and non-parenchymal lymphoid lineages. Diversity of CNS myeloid cell origins CNS macrophages during ontogeny and in adult animals The brain hosts several myeloid populations. In addi- needs to be further determined in future studies. tion to the parenchymal microglia, these cells include The discovery that the brain of the developing mouse perivascular cells, meningeal macrophages and cho- embryo already contains microglia at E9.5 (REFS 26–29) roid plexus macrophages (FIG. 1). Despite the fact that suggested that microglial precursors may originate all of these macrophage populations share numerous from the yolk sac (a structure that is present from an earlier stage of embryogenesis) rather than from HSCs in the fetal liver or bone marrow. Indeed, a population a d e Dendritic of maternally derived committed CD45‑expressing mac- cell rophages can be found in the yolk sac of the embryo Meningeal as early as E7.5 (REFS 11,24) . However, this population Meninges macrophage subsequently decreases in number; it becomes almost Microglial cell undetectable at E9.0 and is later absent in the embryo, suggesting that these cells have a temporal protective effect against intrauterine infections in the embryo24. A second population of extra-embryonic haematopoietic b Choroid plexus cells of zygotic origin in the yolk sac differentiates into macrophage anucleated red blood cells and macrophages24. It took approximately two decades to confirm the yolk sac origin of microglia in sophisticated genetic fate-mapping experiments. By inducing Cre recombi- Choroid plexus nase activity from the runt-related transcription factor (Runx) locus10 or