Microglial subtypes: diversity within the microglial community

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(17)

Published: Aug. 2, 2019

Review2 August 2019Open Access Microglial subtypes: diversity within the microglial community Vassilis Stratoulias orcid.org/0000-0002-9724-6589 Toxicology Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Search for more papers by this author Jose Luis Venero Departamento de Bioquímica y Biología Molecular, Facultad Farmacia, Universidad Sevilla, Spain Instituto Biomedicina Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad Marie-Ève Tremblay Department Molecular Université Laval, Quebec, QC, Canada Axe Neurosciences, Centre Recherche du CHU Québec-Université Bertrand Joseph Corresponding Author [email protected] orcid.org/0000-0001-5655-9979 Information Stratoulias1, Venero2,3, Tremblay4,5 and *,1 1Toxicology 2Departamento 3Instituto 4Department 5Axe *Corresponding author. Tel: +46 703057405; E-mail: The EMBO Journal (2019)38:e101997https://doi.org/10.15252/embj.2019101997 PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Microglia are brain-resident macrophages forming first active immune barrier in central nervous system. They fulfill multiple functions across development adulthood under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure extrinsic cues their environment. However, emerging evidence suggests that display differences not exclusively driven milieu, rather unique properties these cells possess. This intrinsic heterogeneity has been largely overlooked, favoring prevailing view a single-cell type endowed with spectacular plasticity, allowing them acquire thereby numerous health disease. Here, we review might form which each member (or "subtype") displays performs functions. Distinctive features functional implications several subtypes considered, contexts Finally, suggest subtype categorization shall be based on function propose ways studying them. Hence, advocate plasticity (reaction states) (subtypes) should both considered when multitasking microglia. Introduction were introduced scientific literature century ago (Río-Hortega, 1919a,1919b,1919c; Fig 1). During normal physiological conditions, ramified morphology regularly distributed throughout system (CNS; Río-Hortega, 1919b). Upon pathology, transform function, leading cascade "reaction" from hypertrophic ameboid still orients research today (Flanary et al, 2007; Graeber, 2010; With recent advances genetic tools fate mapping (Ginhoux 2010), now tissue-resident CNS arise embryonic yolk sac (Alliot 1999; Schulz 2012; Kierdorf 2013; Perdiguero 2015). colonize murine day (E)9.5 (Tay 2017c) represent self-maintaining long-lived cell population persists months, if entire lifespan organism (Lawson 1992; Ajami 2007, 2011; Mildner Askew 2017; Füger Réu Tay 2017b). Beyond functioning as mediators injury, inflammation, neurodegeneration, roles healthy brain have identified at an exponential rate past decade (Cartier 2014; 2015; Figure 1. Historical overview identificationAlthough originally proposed Rio-Hortega report microglia, it was only recently idea revisited. Download figure PowerPoint exhibit widely differing depending stage life, region, context or Differences number, morphology, gene expression also reported between sexes (Schwarz Crain Lenz Pimentel-Coelho Butovsky Dorfman Hanamsagar Krasemann 2017). Adequate crucial behavioral adaptation environment (Salter Stevens, 2017a). Throughout contribute neurogenesis, neuronal circuit shaping, vascular formation remodeling, maintenance homeostasis 2017c). aging diseases, may become reactive impaired surveillance phagocytosis (Streit, 2002; Koellhoffer Spittau, contribution diseases is associated compromised (e.g., synaptic plasticity; 2017a) processes adaptive brain, yet death tissue damage pathological settings excitotoxicity, oxidative stress, inflammation; Weil 2008). reaction can triggered any kind insults disturbances CNS. Persisting reaction, often proliferation, involved conditions ranging neurodevelopmental disorders, traumatic injuries, infectious tumors, psychiatric neurodegenerative diseases. Depending stressor insult play, process shown proceed differently result sometimes contrasting outcomes (see 2A classical schematic representation, depicting gray surrounded palette colorful representing state). It recognized wide range states, tremendous shift M1/M2 classification used few years (Martinez Gordon, Ransohoff, 2016). According view, would fulfilled through toward phenotypes, molecular signature (Crain Hickman Bennett 2016; Grabert Flowers Galatro Keren-Shaul Hammond 2018; Masuda 2019). pieces indicate different pools acquired during maturation These co-exist steady state undergo further modulation phenotypic transformation response stimuli (Fig 2B). Indeed, beyond adopts stimuli, constitute members properties, perform functions, respond 2C). We distinctive putative "subtypes", structural, ultrastructural, levels, well Furthermore, categorize than signatures markers. candidates validated using methodological workflow recommend. 2. states(A) Currently, homogenous cellular (core circle gray) extremely plastic. status given developmental resulting invariably assume described literature. (B) In updated version here, heterogeneous having specializations. (C) environmental cue, stimulus, expanding and/or changing its specific phenotype. Microglia: fulfilling vast What defines subject intense debate, discussed Box 1 Accumulating indicates naïve responds identically possible assuming predetermined fact, historical perspective, notion had already 1919 his original description 1919b; He noticed some he named "satellite" found close proximity bodies. A later, satellite below, one playing cards deck 3). important acknowledge others, avant-garde scientists, paved way concept (McCluskey Lampson, 2000; Olah Hanisch, Gertig 2014). 1: How define "cell (sub)type" answer "how subtype?" probably closely related question, type?" Traditionally, defined host tissue, lineage, composition. definition term remains debate (Clevers advancement unbiased technologies transcriptome profiling, such high throughput RNAseq mass cytometry improved/related methods), revealed remarkable among traditionally homogeneous. whereas degree proteome sufficient defining subtypes, even topic (Trapnell, Okawa 2018). While allow molecularly subpopulations, approaches require complemented identification populations, order those (sub)types. Worth notice, importance confound states reaction. latter referring various stimuli. shared properties/characteristics other type. Their selective independent microenvironment. two concepts mutually exclusive, stimulus could react new phenotype, i.e., thus adding another level complexity. must steady-state unchallenged propertie(s) translate into function(s). Typically, existing foundation plan, biased respect studies aimed identifying subtype. includes work markers, most importantly staining, sorting, isolation cells. Reverse provide reliable tool studies, but they inherit technical limitations gating flow antibody unspecificity (Luo 2013). On hand, RNAseq, cytometry, electron microscopy useful tools, aware limitation terms providing static dynamics. however combined two-photon vivo imaging insights Serendipitous approach, sporadic non-systematic. All above methodologies subtypes. Considering review, need classifying evident. Deciphering whether variations instructed microenvironment prime importance, following workflow: Fate-mapping strategies visualize selectively subsets, instance non-invasive chronic imaging—could performed longitudinally development, adulthood, aging, conditions—to determine identity subsets phenotypes. remain examined longitudinally, instead another, notably determinants then studied combination protein analyses, ultrastructure, dynamic investigations. 3. Putative specializationsEmerging data support existence genomic, spatial, morphological, anticipate analyzing thoroughly, 1, similar methodology newly discovered ones, will number characteristics targeted prevention treatment. regional Although ubiquitously scattered CNS, distribution varies regions, white matter 1990). differs presence bodies, dendrites axons, myelinated blood vessels. self-renewal turnover rates lipopolysaccharide (LPS) challenge 2017b; Furube tightly transcriptional level, mouse human (Gosselin 2014, Direct variability comes isolated wild-type, adult mice, according area, determined panels pre-selected study, CD11b, CD40, CD45, CD80, CD86, F4/80, TREM2b, CX3CR1, CCR9 compared regions young mice (de Haas all markers expressed varied significantly areas. study rats, levels known showed region-specific profiles (Doorn Similar areas additionally pattern (Butovsky De Biase Additionally, RNA sequencing (RNAseq) cerebral hippocampal analyzed, 47 identified, including belonging (Zeisel findings raise intriguing possibility survival, activity, growth factor release, metabolism, myelination, blood–brain driving differentiation major contributing heterogeneity. Recently, cerebellar clearance ability, genes supporting engulfment catabolism debris (Ayata "type" reminiscent developing disease-associated (DAM) below. By contrast, striatum homeostatic epigenetic mechanisms particular, suppression striatal mediated PRC2, catalyzes repressive chromatin modification histone H3 lysine 27 trimethylation (H3K27me3). ablation PRC2 results emergence absence dying neurons, cortex. aberrant induce motor responses, decreased learning memory, together anxiety seizures characterized CNS-associated (CAM) three CAM Mrc1, Ms4at, Pf4, Stab1, Cbr2, CD163, Fcrls, compartments: leptomeninges, choroid plexus, perivascular space (Jordão Consequently, partly accounted diversity. differential expressions Differential established approach subpopulations type, GABAergic glutamatergic) observed brain. contexts, neighboring state. local cues, interactions neurons inhibitory excitatory) glial (astrocytes, oligodendrocytes, progenitors), slight signaling thresholds. Similarly, peripheral macrophage activation LPS viruses described, where subset concomitantly (Ravasi 2002). addition, directly communicate other, recruitment lead inhibition initially occupying non-overlapping territories changing, improved staining methods showing direct contacts bodies neighbor (for example, see Milior marker adjacent previous challenges considered. For instance, laser injury intact, converging site (Nimmerjahn 2005; Paris migrate cortex (Eyo 2018) cerebellum (Stowell paints layer expression, cannot excluded argue deserves investigation. below: Keratan sulfate proteoglycan (KSPG)-microglia quarter ago, rat constitutive KSPG (Bertolotto 1993), visualized situ 5D4 monoclonal located extracellular matrix surface. suggested control adhesion axonal growth. 5D4-KSPG subpopulation contrary 1993, 1998). Of note, does coincide GFAP, NG2, MAP2, relate strains inbred rats (Jander Stoll, 1996b). mammals, 5D4-KSPG-expressing spinal cord retina 1998; Jander 1996a; Jones Tuszynski, Zhang Foyez 5D4-KSPG-microglia preferential large numbers hippocampus, brainstem, olfactory bulb (OB), detected neonatal mention 5D4-KSPG-negative same (Jones KSPG-reactivity, systematic required confirm 4). 4.Toolbox. Hox8b-microglia differentiates canonical population, spatial temporal 2 ontogeny Hoxb8-microglia). Mice carrying driver Hoxb8-Cre reporter ROSA26-YFP alleles crossed trace YFP-Hoxb8 expression. YFP signal appeared YFP-positive especially OB (Chen 25–40% total YFP-negative Nagarajan Transcriptomic analyses comparing Hoxb8-positive Hoxb8-negative very state, 21 populations (De Hoxb8-microglia express genes, Tmem119, Sall1, Sall3, Gpr56, Ms4a7, hematopoietic Clel12a, Klra2, Lilra5 non-Hoxb8 (Bennett neither expresses Hoxb8 brain; instead, lineage tracer progenitors prior infiltration Selective inactivation grooming behavior, mutant strategy deletion included use Tie2 Cre affect endothelial 2010). More cell-specific prerequisite involvement behavior. (with illustration): Revisiting origin(s) An question arising relates origin(s). Do possess populating do once assumed parenchyma? convincingly derive wave hematopoiesis Hoeffel Sheng Mass 2016), follow stepwise program (Mass Matcovitch-Natan before E9.5 Based literature, differentiate inside parenchyma (a). hypothesis explain microenvironments (inhibitory, oligodendrocytes thresholds, alternative exhibiting infiltrating early investigation, tested (b c). later hypothesis, Capecchi al Hoxb8-microglia-progenitors exist E8.5 Subsequently, transit aorta-gonad-mesonephros fetal liver, expand entry E12.5 (c). lines, CSF1R−/− Erblich 2011) IL2-Tgfb1;Tgfb1−/− (Keren-Shaul 2017) transgenic expected parenchyma. E14.5 exist, Ms4a7 (Hammond great interest investigate subpopulations. zebrafish, waves (Xu Ferrero yolk-sac-equivalent structure origin populate replenished zebrafish (d). div

Language: Английский

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Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2018, Volume and Issue: 13(1)

Published: May 21, 2018

Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM their key regulators may guide pre-clinical experimentation drug discovery.Weighted co-expression network analysis (WGCNA) was applied to existing transcriptomic datasets from neuroinflammatory neurodegenerative mouse models identify modules highly co-expressed genes. These were contrasted known signatures homeostatic microglia reveal novel molecular DAM. Flow cytometric validation studies performed confirm existence distinct sub-populations AD predicted by WGCNA. Gene ontology analyses coupled bioinformatics approaches revealed targets transcriptional favorably modulate neuroinflammation AD. guided in-vivo in-vitro neurodegeneration (5xFAD) determine whether inhibition pro-inflammatory gene expression promotion amyloid clearance feasible. We determined the human relevance these findings integrating our results genome-wide association non-disease post-mortem brain proteomes.WGCNA data a framework activation that anti-inflammatory phenotypes DAM, which we confirmed aging flow cytometry. Pro-inflammatory emerged earlier characterized genes (Tlr2, Ptgs2, Il12b, Il1b), surface marker CD44, potassium channel Kv1.3 (NFkb, Stat1, RelA) while expressed phagocytic (Igf1, Apoe, Myo1e), CXCR4 (LXRα/β, Atf1). As neuro-immunomodulatory strategies, validated LXRα/β agonism blockade ShK-223 peptide promoted inhibited augmented Aβ models. Human AD-risk represented suggesting causal roles for early dysregulation proteins positively associated neuropathology preceded cognitive decline confirming therapeutic inhibiting AD.We provide predictive can characterize therapeutically

Language: Английский

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Immune cell regulation of glia during CNS injury and disease

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(3), P. 139 - 152

Published: Feb. 10, 2020

Language: Английский

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When Immune Cells Turn Bad—Tumor-Associated Microglia/Macrophages in Glioma

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(2), P. 436 - 436

Published: Feb. 1, 2018

As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in progression and controlling anti-tumor immune responses. We review challenges improvements cell models highlight contribution this highly plastic population to immunosuppressive TME, besides their well-known functional regarding glioma invasion angiogenesis. Finally, we summarize first therapeutic interventions target GAMs effect on immunobiology gliomas, focusing interaction with T cells.

Language: Английский

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Immune cells and CNS physiology: Microglia and beyond

The Journal of Experimental Medicine, Journal Year: 2018, Volume and Issue: 216(1), P. 60 - 70

Published: Nov. 30, 2018

Recent advances have directed our knowledge of the immune system from a narrative “self” versus “nonself” to one in which function is critical for homeostasis organs throughout body. This also case with respect central nervous (CNS). CNS immunity exists segregated state, marked partition occurring between brain parenchyma and meningeal spaces. While patrolled by perivascular macrophages microglia, spaces are supplied diverse repertoire. In this review, we posit that such allows neuro–immune crosstalk be properly tuned. Convention may imply an ominous threat function; however, recent studies shown its presence instead steady hand directing optimal performance.

Language: Английский

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Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan

Frontiers in Molecular Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: Jan. 3, 2018

Microglia are the predominant immune response cells and professional phagocytes of central nervous system (CNS) that have been shown to be important for brain development homeostasis. These present a broad spectrum phenotypes across stages lifespan especially in CNS diseases. Their prevalence all neurological pathologies makes it pertinent reexamine their distinct roles during steady-state disease conditions. A major question field is determining whether clustering phenotypical transformation microglial leading causes pathogenesis, or potentially neuroprotective responses onset disease. The recent explosive growth our understanding origin homeostasis microglia, uncovering shaping neural circuitry synaptic plasticity, allows us discuss emerging functions contexts cognitive control psychiatric disorders. mesodermal genetic signature microglia contrast other neuroglial also make them an interesting target therapeutics. Here, we review physiological contribution effects environmental risk factors (e.g., maternal infection, early-life stress, dietary imbalance), impact on disorders initiated Nasu-Hakola disease, hereditary diffuse leukoencephaly with spheroids, Rett syndrome, autism disorders, obsessive-compulsive disorder) adulthood alcohol drug abuse, depressive disorder, bipolar schizophrenia, eating sleep disorders). Furthermore, changes context aging, implication neurodegenerative diseases aged adult Alzheimer's Parkinson's). Taking into account identification microglia-specific markers, availability compounds these selectively vivo, consider prospect intervention via route.

Language: Английский

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Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(7), P. 454 - 468

Published: Jan. 21, 2021

Language: Английский

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To Kill a Microglia: A Case for CSF1R Inhibitors

Trends in Immunology, Journal Year: 2020, Volume and Issue: 41(9), P. 771 - 784

Published: Aug. 10, 2020

Language: Английский

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Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission

Seminars in Cell and Developmental Biology, Journal Year: 2019, Volume and Issue: 94, P. 138 - 151

Published: May 30, 2019

Language: Английский

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Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(11), P. 2472 - 2488

Published: Aug. 19, 2021

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist a vacuum. Instead, pre- postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise four elements of contemporary tetrapartite synapse model. While research this area is still just beginning, accumulating evidence points toward novel role for microglia regulating ECM during normal brain homeostasis, such processes may, turn, become dysfunctional disease. As it relates to synapses, reported modify perisynaptic matrix, diffuse that surrounds dendritic axonal terminals, as well perineuronal nets (PNNs), specialized reticular formations compact enwrap neuronal subsets stabilize proximal synapses. The interconnected relationship between they embedded suggests alterations one structure necessarily affect dynamics other, may need sculpt within. Here, we provide an overview microglial regulation PNNs, propose candidate mechanisms these structures be modified, present implications modifications homeostasis

Language: Английский

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