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Methods in Molecular Biology (Clifton,... 2019Dark microglia, a recently described phenotype, are found in high numbers in nonhomeostatic conditions (e.g., Alzheimer's disease pathology, aging, chronic stress). As a...
Dark microglia, a recently described phenotype, are found in high numbers in nonhomeostatic conditions (e.g., Alzheimer's disease pathology, aging, chronic stress). As a specific protein marker has not yet been defined, they cannot be studied using conventional cellular biology techniques. They are recognized by their unique ultrastructural features visible under electron microscopy. This nanoscale resolution imaging technique allows the identification of cells based on their ultrastructure or immunoreactivity to certain proteins. In this protocol, we describe the steps necessary for the preparation of high-quality brain tissues for transmission electron microscopy, the imaging, the identification of dark microglia, and the ultrastructural analysis of various parameters that can be studied in these cells.
Topics: Alzheimer Disease; Animals; Brain; Microglia; Microscopy, Electron, Transmission
PubMed: 31392680
DOI: 10.1007/978-1-4939-9658-2_8 -
Glia Jun 2018Microglia have diverse actions, ranging from synapse pruning in development to cytotoxic effects in disease. Brain energy metabolism and substrate availability vary... (Review)
Review
Microglia have diverse actions, ranging from synapse pruning in development to cytotoxic effects in disease. Brain energy metabolism and substrate availability vary under normal and disease states, but how these variations influence microglial function is relatively unknown. Microglia, like most other cell types, express the full complement of gene products required for both glycolytic and oxidative metabolism. Evidence suggests that microglia increase aerobic glycolysis and decrease respiration when activated by various stimuli. Mitochondrial function, glucose availability, and glycolytic rate influence pro-inflammatory gene expression at both transcriptional and post-translational levels. These effects are mediated through CtBP, an NADH-sensitive transcriptional co-repressor; through effects on NLRP3 inflammasome assembly and caspase-1 activation; through formation of advanced glycation end-products; and by less well-defined mechanisms. In addition to these transcriptional effects, microglial glucose metabolism is also required for superoxide production by NADPH oxidase, as glucose is the obligate substrate for regenerating NADPH in the hexose monophosphate shunt. Microglia also metabolize acetoacetate and β-hydroxybutyrate, which are generated during fasting or ketogenic diet, and respond to these ketones as metabolic signals. β-Hydroxybutyrate inhibits histone de-acetylases and activates microglial GRP109A receptors. These actions suppress microglia activation after brain injury and promote neuroprotective microglia phenotypes. As our understanding of microglial activation matures, additional links between energy metabolism and microglial function are likely to be identified.
Topics: Animals; Energy Metabolism; Humans; Microglia
PubMed: 29219210
DOI: 10.1002/glia.23271 -
The Journal of Experimental Medicine Jan 2019Glial cells serve as fundamental regulators of the central nervous system in development, homeostasis, and disease. Discoveries into the function of these cells have... (Review)
Review
Glial cells serve as fundamental regulators of the central nervous system in development, homeostasis, and disease. Discoveries into the function of these cells have fueled excitement in glial research, with enthusiastic researchers addressing fundamental questions about glial biology and producing new scientific tools for the community. Here, we outline the pros and cons of in vivo and in vitro techniques to study astrocytes and microglia with the goal of helping researchers quickly identify the best approach for a given research question in the context of glial biology. It is truly a great time to be a glial biologist.
Topics: Animals; Astrocytes; Humans; Microglia; Models, Biological
PubMed: 30541903
DOI: 10.1084/jem.20180200 -
Frontiers in Immunology 2021
Topics: Humans; Microglia; Retina
PubMed: 34539681
DOI: 10.3389/fimmu.2021.758375 -
Methods in Molecular Biology (Clifton,... 2019A century ago, Pío del Río-Hortega discovered that microglial cells are endowed with remarkable dynamic and plastic capabilities. The real-time plasticity of microglia... (Review)
Review
A century ago, Pío del Río-Hortega discovered that microglial cells are endowed with remarkable dynamic and plastic capabilities. The real-time plasticity of microglia could be revealed, however, only during the last 15 years with the development of new transgenic animal models and new molecular and functional analysis methods. Phenotyping microglia in situ with these new tools sealed the fate of the classical two state model of "resting" microglia in physiological conditions and "activated" microglia in pathological conditions. Our current view on functional behavior of microglia takes into account the exquisite reactivity of these immune cells to changes occurring in the CNS in both physiological and pathological conditions. We briefly review here the results and methods that have uncovered the dynamics and versatility of microglial reactivity.
Topics: Animals; Animals, Genetically Modified; Central Nervous System; Humans; Microglia; Neurodegenerative Diseases
PubMed: 31392676
DOI: 10.1007/978-1-4939-9658-2_4 -
Journal of Neuroinflammation Mar 2021There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these... (Review)
Review
There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.
Topics: Animals; Epigenesis, Genetic; Female; Male; Microglia; Rodentia; Sex Characteristics
PubMed: 33731174
DOI: 10.1186/s12974-021-02124-z -
Molecules and Cells Mar 2017Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against... (Review)
Review
Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.
Topics: Animals; Cell Movement; Central Nervous System; Chemotaxis; Humans; Microglia; Signal Transduction
PubMed: 28301917
DOI: 10.14348/molcells.2017.0011 -
BioMed Research International 2017Osteopontin (OPN) is a proinflammatory cytokine that can be secreted from many cells, including activated macrophages and T-lymphocytes, and is widely distributed in... (Review)
Review
Osteopontin (OPN) is a proinflammatory cytokine that can be secreted from many cells, including activated macrophages and T-lymphocytes, and is widely distributed in many tissues and cells. OPN, a key factor in tissue repairing and extracellular matrix remodeling after injury, is a constituent of the extracellular matrix of the central nervous system (CNS). Recently, the role of OPN in neurodegenerative diseases has gradually caused widespread concern. Microglia are resident macrophage-like immune cells in CNS and play a vital role in both physiological and pathological conditions, including restoring the integrity of the CNS and promoting the progression of neurodegenerative disorders. Microglia's major function is to maintain homeostasis and the normal function of the CNS, both during development and in response to CNS injury. Although the functional mechanism of OPN in CNS neurodegenerative diseases has yet to be fully elucidated, most studies suggest that OPN play a role in pathogenesis of neurodegenerative diseases or in neuroprotection by regulating the activation and function of microglia. Here, we summarize the functions of OPN on microglia in response to various stimulations in vitro and in vivo.
Topics: Animals; Central Nervous System; Humans; Microglia; Neurodegenerative Diseases; Osteopontin
PubMed: 28698867
DOI: 10.1155/2017/1879437 -
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system.Neurobiology of Disease May 2021In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue... (Review)
Review
In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue homeostasis. Activation of microglia can result in changes in morphology, phagocytosis capacity, and secretion of cytokines. Furthermore, microglial activation also induces changes to cellular energy demand, which is dependent on the metabolism of various metabolic substrates including glucose, fatty acids, and amino acids. Accumulating evidence demonstrates metabolic reprogramming acts as a key driver of microglial immune response. For instance, microglia in pro-inflammatory states preferentially use glycolysis for energy production, whereas, cells in anti-inflammatory states are mainly powered by oxidative phosphorylation and fatty acid oxidation. In this review, we summarize recent findings regarding microglial metabolic pathways under physiological and pathological circumtances. We will then discuss how metabolic reprogramming can orchestrate microglial response to a variety of central nervous system pathologies. Finally, we highlight how manipulating metabolic pathways can reprogram microglia towards beneficial functions, and illustrate the therapeutic potential for inflammation-related neurological diseases.
Topics: Adaptation, Physiological; Animals; Cellular Reprogramming; Central Nervous System; Humans; Metabolome; Microglia; Phenotype
PubMed: 33556540
DOI: 10.1016/j.nbd.2021.105290 -
Folia Neuropathologica 2020Lipopolysaccharide (LPS) is a potent immunogen when administered locally and/or systemically. The peripheral immunization with LPS could contribute to the progression... (Review)
Review
Lipopolysaccharide (LPS) is a potent immunogen when administered locally and/or systemically. The peripheral immunization with LPS could contribute to the progression of neurological diseases because a strong link between neuroinflammation and dopaminergic degeneration has been found. The switch between the survival and neuronal death in substantia nigra could be related to M1 (neurotoxic) and M2 (neuroprotective) microglia phenotypes. In this review, we present the current findings about microglia roles, biomarkers, and natural or synthetic immune modulators determined in the LPS-based murine model.
Topics: Animals; Cell Differentiation; Disease Models, Animal; Humans; Inflammation; Lipopolysaccharides; Microglia
PubMed: 32729290
DOI: 10.5114/fn.2020.96755