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Neuron Jan 2021The functional contribution of microglia to normal brain development, healthy brain function, and neurological disorders is increasingly recognized. However, until... (Review)
Review
The functional contribution of microglia to normal brain development, healthy brain function, and neurological disorders is increasingly recognized. However, until recently, the nature of intercellular interactions mediating these effects remained largely unclear. Recent findings show microglia establishing direct contact with different compartments of neurons. Although communication between microglia and neurons involves intermediate cells and soluble factors, direct membrane contacts enable a more precisely regulated, dynamic, and highly effective form of interaction for fine-tuning neuronal responses and fate. Here, we summarize the known ultrastructural, molecular, and functional features of direct microglia-neuron interactions and their roles in brain disease.
Topics: Animals; Brain; Brain Diseases; Cell Communication; Humans; Microglia; Neurons
PubMed: 33271068
DOI: 10.1016/j.neuron.2020.11.007 -
Neuron Dec 2021The regenerative capacity of neurons is limited in the central nervous system (CNS), with irreversible neuronal loss upon insult. In contrast, microglia exhibit...
The regenerative capacity of neurons is limited in the central nervous system (CNS), with irreversible neuronal loss upon insult. In contrast, microglia exhibit extraordinary capacity for repopulation. Matsuda et al. (2019) recently reported NeuroD1-induced microglia-to-neuron conversion, aiming to provide an "unlimited" source to regenerate neurons. However, the extent to which NeuroD1 can exert cross-lineage reprogramming of microglia (myeloid lineage) to neurons (neuroectodermal lineage) is unclear. In this study, we unexpectedly found that NeuroD1 cannot convert microglia to neurons in mice. Instead, NeuroD1 expression induces microglial cell death. Moreover, lineage tracing reveals non-specific leakage of similar lentiviruses as previously used for microglia-to-neuron conversion, which confounds the microglia-to-neuron observation. In summary, we demonstrated that NeuroD1 cannot induce microglia-to-neuron cross-lineage reprogramming. We here propose rigid principles for verifying glia-to-neuron conversion. This Matters Arising paper is in response to Matsuda et al. (2019), published in Neuron.
Topics: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Lineage; Mice; Microglia; Neuroglia; Neurons
PubMed: 34875233
DOI: 10.1016/j.neuron.2021.11.008 -
Brain, Behavior, and Immunity Aug 2017Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in...
Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases. It is now well recognized that microglia have functional plasticity and dual phenotypes, proinflammatory M1 and anti-inflammatory M2 phenotypes. Inhibiting the M1 phenotype while stimulating the M2 phenotype has been suggested as a potential therapeutic approach for the treatment of neuroinflammation-related diseases. Resveratrol has been demonstrated to exert anti-inflammatory effects by suppressing M1 microglia activation. However, the role of resveratrol in regulating microglia polarization and the molecular mechanisms involved have not been fully clarified. In this study, we tested whether resveratrol could suppress microglia activation by promoting microglia polarization toward the M2 phenotype via PGC-1α by measuring M1 and M2 markers in vitro and in vivo. Our study demonstrated that resveratrol reduced inflammatory damage and promoted microglia polarization to the M2 phenotype in LPS-induced neuroinflammation. In addition, resveratrol ameliorated LPS-induced sickness behavior in mice. The promoting effects of resveratrol on M2 polarization were attenuated by knocking down PGC-1α. PGC-1α not only suppressed LPS-evoked M1 marker expression by inhibition of NF-κB activity but also increased M2 marker expression by coactivation of the STAT6 and STAT3 pathways. We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.
Topics: Animals; Cell Line, Tumor; Cell Polarity; Encephalitis; Humans; Mice; Microglia; Neuroprotective Agents; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Signal Transduction; Stilbenes
PubMed: 28268115
DOI: 10.1016/j.bbi.2017.03.003 -
Nature Communications Apr 2022Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains...
Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.
Topics: Animals; Mice; Microglia; NF-kappa B; Tauopathies; tau Proteins
PubMed: 35413950
DOI: 10.1038/s41467-022-29552-6 -
Annual Review of Vision Science Sep 2018Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional... (Review)
Review
Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional roles in the retina at different life stages. During development, retinal microglia regulate neuronal survival by exerting trophic influences and influencing programmed cell death. During adulthood, ramified microglia in the plexiform layers interact closely with synapses to maintain synaptic structure and function that underlie the retina's electrophysiological response to light. Under pathological conditions, retinal microglia participate in potentiating neurodegeneration in diseases such as glaucoma, retinitis pigmentosa, and age-related neurodegeneration by producing proinflammatory neurotoxic cytokines and removing living neurons via phagocytosis. Modulation of pathogenic microglial activation states and effector mechanisms has been linked to neuroprotection in animal models of retinal diseases. These findings have led to the design of early proof-of-concept clinical trials with microglial modulation as a therapeutic strategy.
Topics: Animals; Humans; Microglia; Molecular Targeted Therapy; Retina; Retinal Diseases; Retinal Neurons
PubMed: 29852094
DOI: 10.1146/annurev-vision-091517-034425 -
Cell Reports Jan 2022Cx3cr1-driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis of the...
Cx3cr1-driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis of the possible detrimental effects of Cre activity in microglia, surprisingly, remains missing. Here, we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre toxicity, wherein Cre induction, specifically in early postnatal microglia, is detrimental to microglial development, proliferation, and function. Tamoxifen (TAM)-induced Cre activity leads to microglial activation, type 1 interferon (IFN-1) signaling, and increased phagocytosis, causing aberrant synaptic pruning during the early postnatal period and anxious behavior at later age. The detrimental effects of Cre induction are caused by DNA-damage-induced toxicity in microglia and are limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals an age-dependent vulnerability of microglia to Cre activity, thereby highlighting age dependency of Cre action, which could be especially applicable in the broader context of environment-responsive cell types.
Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Brain; CX3C Chemokine Receptor 1; DNA Damage; Genetic Techniques; Integrases; Interferon Type I; Mice; Microglia
PubMed: 35045285
DOI: 10.1016/j.celrep.2021.110252 -
Cells Jul 2020The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia... (Review)
Review
The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
Topics: Animals; Caspases; Central Nervous System; Epigenesis, Genetic; Humans; Inflammation; Microglia; Models, Biological
PubMed: 32709045
DOI: 10.3390/cells9071717 -
Journal of Visualized Experiments : JoVE Feb 2021Microglia are the mononuclear phagocytes in the central nervous system (CNS), which play key roles in maintaining homeostasis and regulating the inflammatory process in...
Microglia are the mononuclear phagocytes in the central nervous system (CNS), which play key roles in maintaining homeostasis and regulating the inflammatory process in the CNS. To study the microglial biology in vitro, primary microglia show great advantages compared to immortalized microglial cell lines. However, microglia isolation from the postnatal mouse brain is relatively less efficient and time-consuming. In this protocol, we provide a quick and easy-to-follow method to isolate primary microglia from the neonatal mouse brain. The overall steps of this protocol include brain dissection, primary brain cell culture, and microglia isolation. Using this approach, researchers can obtain primary microglia with high purity. In addition, the harvested primary microglia were able to respond to the lipopolysaccharides challenge, indicating they retained their immune function. Collectively, we developed a simplified approach to efficiently isolate primary microglia with high purity, which facilitates a wide range of microglial biology investigations in vitro.
Topics: Animals; Animals, Newborn; Brain; Cell Separation; Cells, Cultured; Dissection; Lipopolysaccharides; Mice, Inbred C57BL; Microglia; Mice
PubMed: 33720125
DOI: 10.3791/62237 -
Journal of Visualized Experiments : JoVE Oct 2019This is a protocol for the dual visualization of microglia and infiltrating macrophages in mouse brain tissue. TMEM119 (which labels microglia selectively), when...
This is a protocol for the dual visualization of microglia and infiltrating macrophages in mouse brain tissue. TMEM119 (which labels microglia selectively), when combined with IBA1 (which provides an exceptional visualization of their morphology), allows investigation of changes in density, distribution, and morphology. Quantifying these parameters is important in providing insights into the roles exerted by microglia, the resident macrophages of the brain. Under normal physiological conditions, microglia are regularly distributed in a mosaic-like pattern and present a small soma with ramified processes. Nevertheless, as a response to environmental factors (i.e., trauma, infection, disease, or injury), microglial density, distribution, and morphology are altered in various manners, depending on the insult. Additionally, the described double-staining method allows visualization of infiltrating macrophages in the brain based on their expression of IBA1 and without colocalization with TMEM119. This approach thus allows discrimination between microglia and infiltrating macrophages, which is required to provide functional insights into their distinct involvement in brain homeostasis across various contexts of health and disease. This protocol integrates the latest findings in neuroimmunology that pertain to the identification of selective markers. It also serves as a useful tool for both experienced neuroimmunologists and researchers seeking to integrate neuroimmunology into projects.
Topics: Animals; Brain; Fluorescent Antibody Technique; Homeostasis; Macrophages; Mice; Microglia; Myeloid Cells; Staining and Labeling
PubMed: 31710033
DOI: 10.3791/60510 -
The Journal of Prevention of... 2023Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) plaques and the formation of neurofibrillary... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Increasing evidence has demonstrated that the damage of cell plays an important role in AD. Cell death is a critical phenomenon for physiological functions, which promotes AD pathogenesis. Programmed cell death, including necroptosis, pyroptosis, autophagy, and ferroptosis, have been discovered that have unique biological functions and pathophysiological characteristics. Here, we review the available evidence detailing the mechanisms of programmed microglial death, including pyroptosis, autophagy, and ferroptosis. We also highlight the role of programmed death of microglia during the process of AD and focus on the connection between the disease and cell death.
Topics: Humans; Alzheimer Disease; Microglia; Pyroptosis; Ferroptosis; Autophagy
PubMed: 36641613
DOI: 10.14283/jpad.2023.3