(2018) 21:1171–84. Neuron. doi: 10.1038/nature21029, 84. Science. Blockage of CSF-1R leads to microglia elimination and abnormal circuit connectivity in adult mice (14). (2016) 64:1801–40. Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K(+) channel THIK-1. Molecules participating in cross-talk and their cellular sources are shown in the same colors. doi: 10.1101/cshperspect.a020560, 15. We review this intriguing crosstalk among CNS cells, focusing on astrocytes and microglia and how it contributes to brain development and neurodegenerative diseases. TLR2 expression by astrocytes and microglia … For the central nervous system (CNS), that cell is the neuron. Front Pharmacol. These findings agree with other studies of mouse models and human subjects with R47H TREM2 mutations, consistently finding that microglia surround amyloid plaques, create a putative neuroprotective barrier, and limit plaque-associated neuritic dystrophy (39). doi: 10.2147/JPR.S137131, 80. doi: 10.1016/B978-0-444-63956-1.00008-4, 28. Reactive glia including astrocytes and microglia can express and secrete canonical cytokines such as IL-1β, IL-6, TNF-α, IL-18, TGF-β, and IL-10 after acute tissue injury (80). Interestingly, hematopoietic stem cell—microglia like cells (HSC-MLC) that can, after transfer to CNS, imitate microglia, have been found to be enriched in genes associated with neurological diseases such as Alzheimer Disease (AD) (7). (2017) 96:428–45 e413. ATP mediates rapid microglial response to local brain injury in vivo. (2018) 83:377–87. (2016) 44:505–15.
Microglial TGF-β reduces subacute neuroinflammation after stroke in mice (85). doi: 10.1126/science.aal3589, 62. Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, et al. GFAP, Iba1, and Neuroligin 1 transcripts were used as markers of astrocytes, microglia, and neuron, respectively . TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. (2012) 814:23–45. Secondary to microglial reaction is the activation of astrocytes, which release inflammatory mediators that signal to microglia and can recruit MIG infiltrating hematogenous cells including monocyte-derived macrophages. In the peripheral nervous system, there are two main types of microglia as Schwann cells and satellite cells. RR conceived the topic and outline of the review, recruited AM to participate, supervised the preparation of the drafts and figure, and performed final edits. SPARC antagonizes presynaptic Hevin/SPARCL1, which together with Thrombospondins (TSP1,2) plays an important role in the formation of glutamatergic synapses and provides synaptic stabilization and consolidation. doi: 10.1016/j.immuni.2018.04.016, 33. Chhatbar C, Detje CN, Grabski E, Borst K, Spanier J, Ghita L, et al. The myeloid cells of the central nervous system parenchyma. doi: 10.1126/science.aag2590, 32. Investigation of astrocytes in Huntington Disease (HD) cingulate gyrus using snRNA-Seq, with extensive confirmatory steps for RNA and protein expression, and comprehensive informatics, disclosed three astrocytic states that mapped to transcriptomic clusters (84). Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E, et al. Although they are highly heterogeneous, traditionally, astrocytes are divided into two major groups based on their location and structure. These are oligodendrocytes, astrocytes, ependymal cells, radial glia, Schwann cells, satellite cells, and enteric glia. doi: 10.1371/journal.pbio.3000134, 9. Madry C, Kyrargyri V, Arancibia-Carcamo IL, Jolivet R, Kohsaka S, Bryan RM, et al. For example, ATP derived from astrocytes, which binds P2Y12 and P2Y6 expressed by microglia, promotes microglial phagocytosis, and processes extension in rats (78). Human gene expression profiling obtained from frozen-post mortem AD specimens of superior frontal gyrus using RNA-Seq, has not been found to resemble any disease activation-related gene profile from animal models (41). Reduced levels of presynaptic proteins in exosomes derived from neurons have been reported early in disease, and their quantification in patient plasma may carry prognostic and therapeutic value in neurodegenerative diseases (76). Microglia react to injury through morphological changes, increased proliferation, migration to the target, phagocytosis, activation of the NLRP3 inflammasome, and consequently the release of proinflammatory mediators (30). Glia. During synaptogenesis but also in adult mouse brain, synapses are removed in activity-dependent fashion to refine neural circuits. Acta Neuropathol Commun. In particular, data are scant on whether microglia are involved in CNS vascular pathology. Nat Med. So far the significance of astrocytic domains in health and disease remains unclear. In particular, mice demonstrated a marked phenotype of increased repetitive self-grooming associated with increased GABAergic signaling to astrocytes, and mediated by striatal medium spiny neurons (64). In addition, astrocytes, microglia, and neurons communicate via releasing and responding to extracellular vesicles. Instead, this new profile of human Alzheimer's microglia/myeloid cells (HAM) resembled an “enhanced human aging” transcriptomic phenotype. Microglia rapid and reversible responses to environmental changes are possible in part by activation of ion channels and cell surface receptors (23). Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Recently, new approaches including usage of induced pluripotent stem cell (iPSC) microglia are potentially hopeful as therapeutic strategies (43). The white matter of the cerebral hemispheres and spinal cord consists of myelin, oligodendroglia, astrocytes, microglia, and blood vessels. bioRxiv. Their image in a microscopic cross section is reminiscent of trees with only a few branches - hence the name. TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment. This process has a favorable outcome during acute stress or focal cerebral ischemia, but can limit regeneration at a later stage. Astrocytes … The recognition of astrocytes in the formation of synapses and neural circuits have come from experiments with neuronal cell culture showing the inability of isolated neurons to survive and form synapses without the addition of astrocytes or factors that they secrete (54). Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Astrocyte processes are an inseparable part of synapses, and are well-positioned to respond and/or control the concentration of neurotransmitters via specific membrane receptors and/or their uptake by membrane transporters like AMPA and N-methyl-D-aspartate (NMDA) glutamate transporters (63). Re-establishing the regenerative potential of central nervous system axons in postnatal mice. In addition, astrocytes form long processes with the end feet structures that allow communication with blood vessels, another dense multicellular network. Are they also useful? Koeppen AH. has reported exceptional findings of spatiotemporal transcriptomic heterogeneity of microglia and other brain myeloid cells in six different brain areas and through three developmental stages in mice (12). Oligodendrocytes are a variety of neuroglia cells within the central nervous system. doi: 10.1038/nm.4397, 44. doi: 10.1016/j.neuron.2012.03.026, 17. The drivers of this progress extend from optogenetics and novel imaging techniques through germline genetics, multi-omics and bioinformatics, through innovative cell and organoid models. Schematic overview of some interactions among astrocytes, microglia and neurons. Cell Rep. (2017) 19:1151–64. Estes ML, McAllister AK. Sci Transl Med. (2019) 50:253–71 e256. 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Given that human life-span now extends well-beyond the end of reproductive capacity, it's axiomatic that, while CNS disorders of aging evoke a tissue response, that reaction isn't shaped by evolution to respond specifically to the challenges posed either by aging or by the ongoing pathogenic process. doi: 10.1016/j.neuroscience.2015.04.001, 66. Interestingly, microglial TREM2, implicated in risk for neurodegenerative diseases, is required for microglia to signal to astrocytes to limit their synapse uptake. Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, et al. This data has changed our perspective on microglial regional heterogeneity in adult brains based on previously reported findings. The response largely depends on the disease context. Khakh BS, Sofroniew MV. Glutamine acts as a precursor for glutamate and GABA. (2018) 98:1170–83 e1178. The structural components of astrocytic endfeet also mediate interactions with the BBB. Cytokine-activated astrocytes can promote neurogenesis in adult mice in the sub-ventricular zone (86). BDNF binds to neuronal TrkB, and regulates synaptic transmission and plasticity in mice, including formation of new synapses during learning (21). Interestingly, one population of microglia has displayed highly activated state despite the absence of any pathology and has been restricted to short postnatal period. Molofsky AV, Deneen B. Astrocyte development: a guide for the perplexed. 1. FEBS Open Bio. Microglia plays a major role in chronic pain [ 46 ]. doi: 10.1002/glia.23120, 60. It has been found that in mouse adult brain, striatal microglial phagocytic activity is epigenetically suppressed by the Polycomb repressive complex 2 (PRC2) as compared to the cerebellum (25). Forced expression of PMP2 in the brains of neonatal mice resulted in an increase in diameter and number of astrocytes (47). Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. In this study, it has been found that the highest diversity of subpopulations of microglia with unique molecularity persist during early development. When settled in the brain, peripheral macrophages possess intrinsic ability to express microglia genes, however the true identity of microglia is the function of both the ontogeny and environment (7). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Cross-talk between neurons and microglia or astrocytes has been addressed, however, the manner in which non-neuronal cells communicate and interact remains less well-understood. However, microglial TNF-α at high concentrations causes excitotoxic effects by suppressing astrocyte uptake of glutamate (65). Neuroscience. The response of astrocytes in neurological disorders such as trauma, neuroinflammation, and neurodegeneration as a physiological defense response is called astrogliosis. Immunity. Modeling in mice suggests that microglia constitute a first line of defense, demonstrating activation, and fast recruitment to sites of damage to phagocytose dead cells and debris (87). Condello C, Yuan P, Grutzendler J. Microglia-mediated neuroprotection, TREM2, and Alzheimer's disease: evidence from optical imaging. Microglia and astrocytes cultures are extensively used to examine cellular mechanisms dependent on glial cells (McCarthy and De Vellis, 1980) since, after astrocytes reach confluency, microglia can be efficiently separated by mild trypsinization and shaking (Saura et al., 2003; Moussaud and Draheim, 2010), magnetic separation (Bedi et al., 2013) or immunopanning (Zhang et al., 2016). They are supportive cells of the neurons in the CNS. doi: 10.1002/glia.22836, 49. Every organ possesses one cell type whose properties incarnate and define its function. (2004) 89:1092–100. doi: 10.1038/nn1997, 88. Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Single-nucleus RNA-seq identifies huntington disease astrocyte states. For example, the response to LPS requires TLR-4, which is present on innate immune cells and microglia. The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Cell Rep. (2018) 25:118–29 e114. TREM2 sustains metabolic fitness, energy homeostasis, proliferation, and survival in mouse microglia through mTOR signaling. (2014) 94:1077–98. Microglia (cyan) working hard to clear up damaged myelin (yellow) following myelin injury in rat brain. In the context of inflammatory neurological diseases, cross-talk between astrocytes and microglia seems particularly important. Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, et al. Besides complement dependent pruning, mechanisms based on CX3CL1—CX3CR1 is also involved in synaptic elimination and maturation (17, 18). (2018) 8:843–53. doi: 10.1016/j.neuron.2016.09.016, 40. ATP modifies the proteome of extracellular vesicles released by microglia and influences their action on astrocytes. No use, distribution or reproduction is permitted which does not comply with these terms. (2013) 12:426–39. (2019). Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. Astrocyte activity can be visualized by imaging changes in intracellular Ca2+ levels and it is widely accepted that the dynamic communication between astrocytes and neurons studied in murine models is maintained by purinergic receptors and is fortified by the calcium waves and oscillations (49). Salter MW, Stevens B. Microglia emerge as central players in brain disease. doi: 10.1002/glia.23664, 63. Kopec AM, Smith CJ, Ayre NR, Sweat SC, Bilbo SD. The goal of studying these intercellular communications is to promote our ability to combat incurable neurological disorders. A recent study by Li et al. Binding of ATP by microglia and astrocytes, contingent on which purinergic receptor is expressed, may evoke calcium currents in both cell types, and the production of inflammatory cytokines by cultured dorsal horn microglia (79). doi: 10.1016/j.devcel.2012.10.027, 21. Mice lacking TREM2 show reduced synapses resulting from loss of this regulatory mechanism during development. Astrocytes and oligodendrocytes are not only supportive cells that release trophic factors or regulate energy metabolism, but they also actively modulate critical neuronal processes and functions in the tripartite synapse. In the adult brain, astrocytes continue to guard proper functioning of the brain and neurons. The second group contains fibrous astrocytes present in the white matter, contacting Ranvier nodes, and myelinated axonal pathways, where they support myelination (51). Synaptic pruning by microglia is necessary for normal brain development. Reactive astrocytes lost their domain organization in experimental models of epilepsy, but are preserved in the animal model of AD. (2017) 356:eaal3222. Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y1 receptor downregulation. doi: 10.1101/cshperspect.a020370, 55. In murine and human brain, microglial processes contact neuronal somata at specialized junctions regulated by purinergic signaling in microglia (22). [10,11] Microglia and astrocytes are two major types of glial cells involved in the regulation of the immune response to pathological processes in the brain. 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J Clin Invest. doi: 10.1038/nri.2017.125, 6. Both microglia and astrocytes are considered to be part of the innate immune system based on their ability to produce immunomodulators and expression of receptors associated with innate immunity, such as complement receptors or Toll-like Receptors (TLRs). Astrocytes (from Greek astron means star) have gained this name due to their characteristic star-like shape with long processes connecting with almost all types of CNS cells. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior. The presynaptic activity and upregulation of synaptic transmission is partially maintained by cholesterol, lipid synthesized by astrocytes, which in combination with ApoE is transported to neurons. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. 11:1416. doi: 10.3389/fimmu.2020.01416. A previous report used conventional immunohistochemistry to show that CCR2 is exclusively expressed by astrocytes, but not infiltrating monocytes/microglia or neurons, in the spinal cords of ALS model mice. Microglia communicate with neurons and neighboring cells via neurotransmitter receptors, purinoreceptors and ion channels. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. They represent the largest group of glial cells with one astrocyte touching base with nearly 2 million synapses in the human brain. doi: 10.4049/jimmunol.1400716, 14. (2016) 353:777–83. It remains controversial whether circulating monocytes expressing CCR2 infiltrate the central nervous system (CNS) and contribute to pathogenicity of amyotrophic lateral sclerosis (ALS). Normal astrogliosis after brain injury is associated with inositol 1,4,5-triphosphate (IP3)-dependent signaling pathway and N-cadherin upregulation (67). Cell. (2016) 323:43–61. For example, microglia promote astrogliogenesis of NSCs in vitro (Gu et al., 2011), whereas, astrocytes stimulate neuronal differentiation of NSCs (Liu et al., 2012). Microglia display a broad spectrum of phenotypes depending on environmental assemblage. Microglia contain branched cytoplasmic processes and function as the macrophages of the central nervous system and play an important phagocytic role. They have different developmental origins: astrocytes are derived from neuroepithelial progenitors, whereas microglia are derived from a hematopoietic common myeloid progenitor that enters the brain during embryogenesis (reviewed in [ 1, 2 ]). Immunity. Synapses are interconnecting elements between two neurons that allow the transmission of signals in neuronal networks. In the adult brain, microglia perform many functions as diverse as neuronal support, synaptic modulation, reorganization of neuronal circuitry, and the production of significant amounts of antimicrobial peptides. Ontogeny and functions of central nervous system macrophages. Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Astrocytes take in glutamate, convert it to glutamine and in this form shuttle it back to neurons. Neuron. Contingent on receptor expression, these cytokines function in both autocrine and paracrine manner. Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Reactive astrocytes upregulate GFAP and undergo morphological changes leading to the formation of glial scars, which may limit damage within the affected area (88). Introduction. (2018) 21:1049–60. Role of microglia and astrocytes in the process of neuroinflammation. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. SPARC limits the levels of AMPA receptors (postsynaptic glutamate receptors, whose activation leads to strengthening of the synapse), ultimately modulating the activity-dependent elimination of synapses in mice (56). Neuroscience. Nature. Nature. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Drago F, Lombardi M, Prada I, Gabrielli M, Joshi P, Cojoc D, et al. Protection against the further spread of viral infection has been maintained by an early innate barrier composed mainly of microglia, whose response was regulated by strong IFNAR signaling from neurons and weaker signaling from astrocytes (90). Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, et al. Migration of microglia progenitors to developing CNS is followed by rapid multiplication and creation of a pool of residual cells that are long-lived and have the ability to renew independently of the hematopoietic system. (2018) 154:129–49. Nat Commun. Li Q, Barres BA. Nat Rev Neurosci. Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, et al. Each of the populations of non-neuronal cells of the adult CNS are remarkably adapted to support neuronal function: astrocytes maintain ionic and neurotransmitter homeostasis, refine synaptic connections, and provide neuronal metabolic substrates; microglia monitor synaptic elements and networks, responding to dyshomeostasis by inducing or removing synaptic elements and by modulating neuronal activity; oligodendrocytes elaborate myelin sheaths, which protect and nourish myelinated neuritic segments. doi: 10.1172/JCI121901, 31. P2Y12 and P2Y13 receptors involved in ADPbetas induced the release of IL-1β, IL-6 and TNF-α from cultured dorsal horn microglia. doi: 10.1084/jem.20182042, 43. Neuron. Local elimination of activated astrocytes improved axonal regeneration after injury in postnatal mice (70). Impact Factor 5.085 | CiteScore 5.4More on impact ›, Understanding the Roles of Glia and Circulating Leukocytes in Neurodegenerative Diseases
Neuron. Brain Pathol. With regard to ontogeny, microglia differ significantly from their macrophage relatives in other tissues. Microglia come from yolk sac erythro-myeloid progenitors and settle the brain early in brain development before the blood-brain-barrier (BBB) closure (4). Nature. Like macrophages and peripheral stroma, at first glance astrocytes and microglia have little in common. Activated astrocytes are characterized by a different molecular pattern, morphology, and function as compared to their normal counterparts. Neurons, Astrocytes, Microglia: High Quality primary cells source In the field of neurosciences, increasing research is being undertaken on neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases, as well as on nerve injury and regeneration. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. In addition, glucose stored exclusively in astrocytes in the form of glycogen allows the use of lactate as a source of energy not only for neurons, but also for other brain cells (53). Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. (2) Binding of IgG activates the astrocyte and induces AQP4 internalization. doi: 10.1016/j.neuron.2018.08.015, 65. Mol Neurodegener. Intense activation of microglia and astrocytes after intracerebral transplantation has been strongly associated with graft rejection. Astrocytes are generated in the ventricular zone from the same progenitor cells as neurons and oligodendrocytes, called radial glial cells. doi: 10.1152/physrev.00041.2013, 68. De Pitta M, Brunel N, Volterra A. Astrocytes: orchestrating synaptic plasticity? Clarke LE, Barres BA. doi: 10.1126/science.aat0473, 54. Nat Neurosci. Whether glial cells adopt a phenotype that aggravates tissue injury or promotes brain repair, most likely depends on a basic set of factors, such as the nature of the damaging element, severity and time course of injury, and precise constellation of signals from the environment.