Microglia states and nomenclature: A field at its crossroads

Neuron, Год журнала: 2022, Номер 110(21), С. 3458 - 3483

Опубликована: Ноя. 1, 2022

Язык: Английский

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Overview of General and Discriminating Markers of Differential Microglia Phenotypes

Frontiers in Cellular Neuroscience, Год журнала: 2020, Номер 14

Опубликована: Авг. 6, 2020

Inflammatory processes and microglia activation accompanies most of the pathophysiological diseases in central nervous system. It is proven that glial pathology precedes even drives development multiple neurodegenerative conditions. A growing number studies point out importance brain as well physiological functioning. Those resident immune cells are divergent from peripherally infiltrated macrophages, but their precise situ discrimination surprisingly difficult. Microglia heterogeneity visible especially morphology, cell density particular structures, also expression cellular markers. This often determines role physiology or The species differences between rodent human markers add complexity to whole picture. Furthermore, due activation, shows a broad spectrum phenotypes ranging pro-inflammatory, potentially cytotoxic M1, anti-inflammatory, scavenging regenerative M2. distinction specific nowadays essential study microglial functions tissue state such quickly changing environment. Due overwhelming data on sets available for studies, choice appropriate scientific challenge. review gathers, classifies describes known recently discovered protein expressed by different phenotypes. Presented include qualitative semi-quantitative, general specific, surface intracellular proteins secreted molecules. Information provided here creates comprehensive practical guide trough current knowledge will allow choose proper, more detailed neuroinflammatory mechanisms various, physiological, pathological, Both, basic research clinical medicine, need clearly described validated molecular phenotype, diagnostics, treatment prevention engaging glia activation.

Язык: Английский

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Microglial subtypes: diversity within the microglial community

The EMBO Journal, Год журнала: 2019, Номер 38(17)

Опубликована: Авг. 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

Язык: Английский

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Microglial regional heterogeneity and its role in the brain

Molecular Psychiatry, Год журнала: 2019, Номер 25(2), С. 351 - 367

Опубликована: Ноя. 26, 2019

Abstract Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities adult microglia their cell number, cellular subcellular structures, molecular signature as well relevant functions discovered. But recent transcriptomic studies using bulk RNAseq single-cell produced conflicting results on region-specific signatures microglia. It is highly speculative whether such spatial contributes varying sensitivities individual same physiological pathological signals CNS regions, hence underlie relevance for disease development. This review aims thoroughly summarize up-to-date knowledge specific topic provide some insights potential mechanisms, starting from microgliogenesis. Understanding regional context diverse neighboring neurons other glia may an important clue future development innovative therapies neuropsychiatric disorders.

Язык: Английский

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Remyelination in multiple sclerosis: from basic science to clinical translation

The Lancet Neurology, Год журнала: 2020, Номер 19(8), С. 678 - 688

Опубликована: Июль 20, 2020

Язык: Английский

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Microglia: Agents of the CNS Pro-Inflammatory Response

Cells, Год журнала: 2020, Номер 9(7), С. 1717 - 1717

Опубликована: Июль 17, 2020

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though research spans over century, last two decades have increased our understanding exponentially. Here, we discuss phenotypic transformation from homeostatic towards reactive microglia, initiated specific ligand binding pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering expressed on myeloid cells-2 (TREM2), as well signaling pathways triggered such caspase-mediated response. Additionally, new disciplines epigenetics and immunometabolism provided us with more holistic view how changes in DNA methylation, microRNAs, metabolome may influence This review aimed current knowledge different angles, recent highlights role exosomes spreading neuroinflammation emerging techniques positron emission tomography (PET) scanning use human generated induced pluripotent stem cells (iPSCs). Finally, also thoughts impact

Язык: Английский

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A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Март 31, 2020

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout AD its continuum. Large-scale genome-wide association studies point out several genetic variants - TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, HLA-DRB5-HLA-DRB1 potentially linked to neuroinflammation. Most these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins cell turn-over, synaptic activity, lipid metabolism, vesicle trafficking. Proteomic indicate that a plethora interconnected aberrant molecular pathways, set off perpetuated by TNF-α, TGF-β, IL-1β, receptor protein Microglia astrocytes key cellular drivers regulators Under physiological conditions, they important for neurotransmission homeostasis. In AD, there is turning pathophysiological evolution where glial cells sustain an overexpressed inflammatory response synergizes with amyloid-β tau accumulation, drives synaptotoxicity neurodegeneration self-reinforcing manner. Despite strong therapeutic rationale, previous trials investigating compounds anti-inflammatory properties, including non-steroidal drugs (NSAIDs) did not achieve primary efficacy endpoints. It conceivable study design issues, lack diagnostic accuracy biomarkers target population identification proof-of-mechanism may partially explain negative outcomes. However, recent meta-analysis indicates potential biological effect NSAIDs. this regard, candidate fluid neuroinflammation under analytical/clinical validation, i.e. MCP-1, IL-6, TNF-α complexes, YKL-40. PET radio-ligands investigated accomplish in-vivo longitudinal regional exploration Biomarkers tracking different pathways (body matrixes) along brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between other mechanisms. Robust biomarker-drug co-development pipelines expected enrich large-scale testing new-generation active, directly or indirectly, on targets displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), AL003 (anti-CD33 antibody). As next step, taking advantage breakthrough multimodal techniques coupled systems biology approach path pursue developing individualized strategies targeting framework precision medicine.

Язык: Английский

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Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury

Journal of Neuroinflammation, Год журнала: 2021, Номер 18(1)

Опубликована: Янв. 5, 2021

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation neuroinflammation are key cellular events following TBI, but the regulatory functional mechanisms still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), member Tyro-Axl-Mer (TAM) family receptor kinases, regulates multiple features microglial/macrophage physiology. However, its function in regulating innate immune response M1/M2 polarization TBI has been addressed. The present study aimed to evaluate role Mer TBI. Methods controlled cortical impact (CCI) mouse model was employed. siRNA intracerebroventricularly administered, recombinant protein S (PS) intravenously applied for intervention. neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry confocal microscopy analysis, Nissl Fluoro-Jade B staining, water content measurement, contusion volume assessment were performed. Results upregulated acute stage Mechanistically, activates signal transducer activator transcription 1 (STAT1)/suppressor cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition markedly decreases M2-like while increases M1-like polarization, which exacerbates secondary damage sensorimotor deficits after Recombinant PS exerts beneficial effects mice through activation. Conclusions an important regulator neuroinflammation, may be considered as potential target therapeutic intervention

Язык: Английский

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Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH

Science, Год журнала: 2022, Номер 377(6601), С. 56 - 62

Опубликована: Июнь 30, 2022

The human cerebral cortex has tremendous cellular diversity. How different cell types are organized in the and how organization varies across species remain unclear. In this study, we performed spatially resolved single-cell profiling of 4000 genes using multiplexed error-robust fluorescence situ hybridization (MERFISH), identified more than 100 transcriptionally distinct populations, generated a molecularly defined atlas middle superior temporal gyrus. We further explored cell-cell interactions arising from soma contact or proximity type–specific manner. Comparison mouse cortices showed conservation laminar cells differences somatic species. Our data revealed human-specific patterns markedly increased enrichment for between neurons non-neuronal cortex.

Язык: Английский

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Microglia Phenotypes in Aging and Neurodegenerative Diseases

Cells, Год журнала: 2022, Номер 11(13), С. 2091 - 2091

Опубликована: Июнь 30, 2022

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays fundamental role in mediating the onset progression disease. Microglia, which function as first-line immune guardians central nervous system (CNS), are drivers neuroinflammation. Numerous human postmortem studies vivo imaging analyses have shown chronically activated microglia patients with various acute chronic neuropathological diseases. While microglial activation common feature NDs, exact pathological states complex often contradictory. However, there consensus that play biphasic conditions, detrimental protective phenotypes, overall response different phenotypes depends on nature duration inflammatory insult, well stage disease development. This review provides comprehensive overview current research responses health, aging, special emphasis heterogeneous phenotypic such hemorrhagic stroke (HS), Alzheimer's (AD), Parkinson's (PD). The primary focus translational preclinical animal models bulk/single-cell transcriptome samples. Additionally, this covers key receptors signaling pathways potential therapeutic targets to regulate during aging NDs. age-, sex-, species-specific differences will be briefly reviewed.

Язык: Английский

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