-
Neural Development Dec 2019Microglia are increasingly shown to be key players in neuron development and synapse connectivity. However, the underlying mechanisms by which microglia regulate neuron... (Review)
Review
Microglia are increasingly shown to be key players in neuron development and synapse connectivity. However, the underlying mechanisms by which microglia regulate neuron function remain poorly understood in part because such analysis is challenging in the brain where neurons and synapses are intermingled and connectivity is only beginning to be mapped. Here, we discuss the features and function of microglia in the ordered mammalian retina where the laminar organization of neurons and synapses facilitates such molecular studies. We discuss microglia origins and consider the evidence for molecularly distinct microglia subpopulations and their potential for differential roles with a particular focus on the early stages of retina development. We then review the models and methods used for the study of these cells and discuss emerging data that link retina microglia to the genesis and survival of particular retina cell subtypes. We also highlight potential roles for microglia in shaping the development and organization of the vasculature and discuss cellular and molecular mechanisms involved in this process. Such insights may help resolve the mechanisms by which retinal microglia impact visual function and help guide studies of related features in brain development and disease.
Topics: Animals; Microglia; Retina
PubMed: 31888774
DOI: 10.1186/s13064-019-0137-x -
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 -
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 -
Frontiers in Immunology 2021
Topics: Humans; Microglia; Retina
PubMed: 34539681
DOI: 10.3389/fimmu.2021.758375 -
Frontiers in Immunology 2022Microglia are mononuclear phagocytes of mesodermal origin that migrate to the central nervous system (CNS) during the early stages of embryonic development. After... (Review)
Review
Microglia are mononuclear phagocytes of mesodermal origin that migrate to the central nervous system (CNS) during the early stages of embryonic development. After colonizing the CNS, they proliferate and remain able to self-renew throughout life, maintaining the number of microglia around 5-12% of the cells in the CNS parenchyma. They are considered to play key roles in development, homeostasis and innate immunity of the CNS. Microglia are exceptionally diverse in their morphological characteristics, actively modifying the shape of their processes and soma in response to different stimuli. This broad morphological spectrum of microglia responses is considered to be closely correlated to their diverse range of functions in health and disease. However, the morphophysiological attributes of microglia, and the structural and functional features of microglia-neuron interactions, remain largely unknown. Here, we assess the current knowledge of the diverse microglial morphologies, with a focus on the correlation between microglial shape and function. We also outline some of the current challenges, opportunities, and future directions that will help us to tackle unanswered questions about microglia, and to continue unravelling the mysteries of microglia, in all its shapes.
Topics: Microglia; Central Nervous System; Neurons; Homeostasis
PubMed: 36341385
DOI: 10.3389/fimmu.2022.997786 -
Frontiers in Immunology 2022Recent epidemiological studies show a noticeable correlation between chronic microbial infections and neurological disorders. However, the underlying mechanisms are... (Review)
Review
Recent epidemiological studies show a noticeable correlation between chronic microbial infections and neurological disorders. However, the underlying mechanisms are still not clear due to the biological complexity of multicellular and multiorgan interactions upon microbial infections. In this review, we show the infection leading to neurodegeneration mediated by multiorgan interconnections and neuroinflammation. Firstly, we highlight three inter-organ communications as possible routes from infection sites to the brain: nose-brain axis, lung-brain axis, and gut-brain axis. Next, we described the biological crosstalk between microglia and astrocytes upon pathogenic infection. Finally, our study indicates how neuroinflammation is a critical player in pathogen-mediated neurodegeneration. Taken together, we envision that antibiotics targeting neuro-pathogens could be a potential therapeutic strategy for neurodegeneration.
Topics: Astrocytes; Brain; Humans; Microglia; Neuroinflammatory Diseases
PubMed: 36052093
DOI: 10.3389/fimmu.2022.907804 -
Trends in Molecular Medicine Feb 2019Microglia are the resident immune cells that maintain brain homeostasis and contribute to neurodegenerative disorders. Recent studies of microglia at transcriptomic and... (Review)
Review
Microglia are the resident immune cells that maintain brain homeostasis and contribute to neurodegenerative disorders. Recent studies of microglia at transcriptomic and epigenetic levels revealed specific molecular pathways that regulate microglia development, maturation, and reactive states. The transcription factor PU.1 plays a key role in regulating several microglial functions. Environmental factors such as microbiota, early life stress, and maternal immune activation can dysregulate PU.1 and innate immune response. This review discusses the epigenetic regulation of key transcriptional factors in human and murine microglia, highlighting their networks for shaping the microglial function. PU.1 and other microglia-specific transcriptional factors can be further studied to determine their therapeutic applications in neurologic disorders.
Topics: Animals; Epigenesis, Genetic; Gene Regulatory Networks; Humans; Microglia; Nervous System Diseases; Proto-Oncogene Proteins; Trans-Activators; Transcriptional Activation; Transcriptome
PubMed: 30578089
DOI: 10.1016/j.molmed.2018.11.004 -
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