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Translational Neurodegeneration Nov 2020Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and... (Review)
Review
Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.
Topics: Animals; Astrocytes; Humans; Inflammation; Inflammation Mediators; Microglia; Neurodegenerative Diseases
PubMed: 33239064
DOI: 10.1186/s40035-020-00221-2 -
Immunity Oct 2021As resident macrophages of the central nervous system (CNS), microglia are associated with diverse functions essential to the developing and adult brain during... (Review)
Review
As resident macrophages of the central nervous system (CNS), microglia are associated with diverse functions essential to the developing and adult brain during homeostasis and disease. They are aided in their tasks by intricate bidirectional communication with other brain cells under steady-state conditions as well as with infiltrating peripheral immune cells during perturbations. Harmonious cell-cell communication involving microglia are considered crucial to maintain the healthy state of the tissue environment and to overcome pathology such as neuroinflammation. Analyses of such intercellular pathways have contributed to our understanding of the heterogeneous but context-associated microglial responses to environmental cues across neuropathology, including inflammatory conditions such as infections and autoimmunity, as well as immunosuppressive states as seen in brain tumors. Here, we summarize the latest evidence demonstrating how these interactions drive microglia immune and non-immune functions, which coordinate the transition from homeostatic to disease-related cellular states.
Topics: Animals; Central Nervous System; Homeostasis; Humans; Microglia
PubMed: 34644556
DOI: 10.1016/j.immuni.2021.09.014 -
Annual Review of Immunology 2014Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia.... (Review)
Review
Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia. Although microglia were first described as ramified brain-resident phagocytes, research conducted over the past century has expanded considerably upon this narrow view and ascribed many functions to these dynamic CNS inhabitants. Microglia are now considered among the most versatile cells in the body, possessing the capacity to morphologically and functionally adapt to their ever-changing surroundings. Even in a resting state, the processes of microglia are highly dynamic and perpetually scan the CNS. Microglia are in fact vital participants in CNS homeostasis, and dysregulation of these sentinels can give rise to neurological disease. In this review, we discuss the exciting developments in our understanding of microglial biology, from their developmental origin to their participation in CNS homeostasis and pathophysiological states such as neuropsychiatric disorders, neurodegeneration, sterile injury responses, and infectious diseases. We also delve into the world of microglial dynamics recently uncovered using real-time imaging techniques.
Topics: Animals; Cell Differentiation; Homeostasis; Humans; Infections; Microglia; Neurodegenerative Diseases; Obsessive-Compulsive Disorder
PubMed: 24471431
DOI: 10.1146/annurev-immunol-032713-120240 -
Cell Oct 2019Microglia were first recognized as a distinct cell population in the CNS one century ago. For a long time, they were primarily considered to be phagocytes responsible... (Review)
Review
Microglia were first recognized as a distinct cell population in the CNS one century ago. For a long time, they were primarily considered to be phagocytes responsible for removing debris during CNS development and disease. More recently, advances in imaging and genetics and the advent of single-cell technologies provided new insights into the much more complex and fascinating biology of microglia. The ontogeny of microglia was identified, and their functions in health and disease were better defined. Although many questions about microglia and their roles in human diseases remain unanswered, the prospect of targeting microglia for the treatment of neurological and psychiatric disorders is tantalizing.
Topics: Animals; Homeostasis; Humans; Microglia; Neurodegenerative Diseases; Neurogenesis; Transcriptome
PubMed: 31585077
DOI: 10.1016/j.cell.2019.08.053 -
The Journal of Cell Biology Feb 2018Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data... (Review)
Review
Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.
Topics: Alzheimer Disease; Animals; Brain; Humans; Microglia
PubMed: 29196460
DOI: 10.1083/jcb.201709069 -
Annual Review of Immunology Apr 2017Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but... (Review)
Review
Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases.
Topics: Animals; Biological Therapy; Brain; Central Nervous System; Cytokines; Homeostasis; Humans; Microglia; Neurodegenerative Diseases; Neurogenic Inflammation
PubMed: 28226226
DOI: 10.1146/annurev-immunol-051116-052358 -
Cell Reports Feb 2020Microglia are resident immune cells in the central nervous system (CNS) that are capable of carrying out prominent and various functions during development and adulthood... (Review)
Review
Microglia are resident immune cells in the central nervous system (CNS) that are capable of carrying out prominent and various functions during development and adulthood under both homeostatic and disease conditions. Although microglia are traditionally thought to be heterogeneous populations, which potentially allows them to achieve a wide range of responses to environmental changes for the maintenance of CNS homeostasis, a lack of unbiased and high-throughput methods to assess microglia heterogeneity has prevented the study of spatially and temporally distributed microglia subsets. The recent emergence of novel single-cell techniques, such as cytometry by time-of-flight mass spectrometry (CyTOF) and single-cell RNA sequencing, enabled scientists to overcome such limitations and reveal the surprising context-dependent heterogeneity of microglia. In this review, we summarize the current knowledge about the spatial, temporal, and functional diversity of microglia during development, homeostasis, and disease in mice and humans.
Topics: Aging; Animals; Brain; Homeostasis; Humans; Macrophages; Microglia; Single-Cell Analysis
PubMed: 32023447
DOI: 10.1016/j.celrep.2020.01.010 -
Nature Neuroscience Oct 2018The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the... (Review)
Review
The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer's, Parkinson's, Huntington's, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy.
Topics: Animals; Humans; Inflammation; Microglia; Neurodegenerative Diseases
PubMed: 30258234
DOI: 10.1038/s41593-018-0242-x -
Immunity Feb 2020Recent years have witnessed a revolution in our understanding of microglia biology, including their major role in the etiology and pathogenesis of neurodegenerative... (Review)
Review
Recent years have witnessed a revolution in our understanding of microglia biology, including their major role in the etiology and pathogenesis of neurodegenerative diseases. Technological advances have enabled the identification of microglial signatures in health and disease, including the development of new models to investigate and manipulate human microglia in vivo in the context of disease. In parallel, genetic association studies have identified several gene risk factors associated with Alzheimer's disease that are specifically or highly expressed by microglia in the central nervous system (CNS). Here, we discuss evidence for the effect of stress, diet, sleep patterns, physical activity, and microbiota composition on microglia biology and consider how lifestyle might influence an individual's predisposition to neurodegenerative diseases. We discuss how different lifestyles and environmental factors might regulate microglia, potentially leading to increased susceptibility to neurodegenerative disease, and we highlight the need to investigate the contribution of modern environmental factors on microglia modulation in neurodegeneration.
Topics: Aging; Animals; Central Nervous System; Circadian Rhythm; Exercise; Feeding Behavior; Genetic Predisposition to Disease; Humans; Life Style; Microbiota; Microglia; Neurodegenerative Diseases; Sleep; Stress, Psychological
PubMed: 31924476
DOI: 10.1016/j.immuni.2019.12.003 -
Frontiers in Immunology 2022Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or... (Review)
Review
Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia's phenotype to foster neuroprotection.
Topics: Axons; Humans; Microglia; Nerve Regeneration; Neuroinflammatory Diseases; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 35309305
DOI: 10.3389/fimmu.2022.860070