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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 -
Ageing Research Reviews Nov 2022Vascular dementia (VaD) is a second most common form of age-related dementia. It is characterized by cognitive impairment associated with vascular pathology, symptoms... (Review)
Review
Vascular dementia (VaD) is a second most common form of age-related dementia. It is characterized by cognitive impairment associated with vascular pathology, symptoms mainly caused by cerebral damage due to inadequate blood flow to the brain. The pathogenesis of VaD is complex, and a growing body of literature emphasizes on the involvement of microglia in disease development and progression. Here, we review the current knowledge on the role of microglia in regulating neuroinflammation under the pathogenesis of VaD. The commonly used animal and cell models for understanding the disease pathogenesis were summarized. The mechanisms by which microglia contribute to VaD are multifactorial, and we specifically focus on some of the predominant functions of microglia, including chemotaxis, secretory property, phagocytosis, and its crosstalk with other neurovascular unit cells. Finally, potential therapeutic strategies targeting microglia-modulated neuroinflammation are discussed.
Topics: Animals; Brain; Cognitive Dysfunction; Dementia, Vascular; Humans; Microglia
PubMed: 36113763
DOI: 10.1016/j.arr.2022.101734 -
Glia Jul 2021Microglia are innate immune cells of the central nervous system that sense extracellular cues. Brain injuries, inflammation, and pathology evoke dynamic structural... (Review)
Review
Microglia are innate immune cells of the central nervous system that sense extracellular cues. Brain injuries, inflammation, and pathology evoke dynamic structural responses in microglia, altering their morphology and motility. The dynamic motility of microglia is hypothesized to be a critical first step in sensing local alterations and engaging in pattern-specific responses. Alongside their pathological responses, microglia also sense and regulate neuronal activity. In this review, we consider the extracellular molecules, receptors, and mechanisms that allow microglia to sense neuronal activity changes under both hypoactivity and hyperactivity. We also highlight emerging in vivo evidence that microglia regulate neuronal activity, ranging from physiological to pathophysiological conditions. In addition, we discuss the emerging role of calcium signaling in microglial responses to the extracellular environment. The dynamic function of microglia in monitoring and influencing neuronal activity may be critical for brain homeostasis and circuit modification in health and disease.
Topics: Brain; Calcium Signaling; Central Nervous System; Microglia; Neurons
PubMed: 33369790
DOI: 10.1002/glia.23961 -
Trends in Molecular Medicine Nov 2019Originally hypothesized to function solely as immunologic responders within the central nervous system (CNS), emerging evidence has revealed that microglia have more... (Review)
Review
Originally hypothesized to function solely as immunologic responders within the central nervous system (CNS), emerging evidence has revealed that microglia have more complex roles in normal brain development and in the context of disease. In health, microglia influence neural progenitor fate decisions, astrocyte activation, neuronal homeostasis, and synaptogenesis. In the setting of brain disease, including autism, brain tumors, and neurodegenerative disorders, microglia undergo substantial morphological, molecular, and functional changes, which establish new biological states relevant to disease pathogenesis and progression. In this review, we discuss the function of microglia in health and disease and outline a conceptual framework for elucidating their specific contributions to nervous system pathobiology.
Topics: Aging; Animals; Astrocytes; Autistic Disorder; Biomarkers; Brain; Brain Neoplasms; Cell Differentiation; Cellular Microenvironment; Central Nervous System; Homeostasis; Humans; Inflammation Mediators; Microglia; Neurodegenerative Diseases; Neurons; Synapses
PubMed: 31597593
DOI: 10.1016/j.molmed.2019.08.013 -
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 -
Seminars in Cell & Developmental Biology Oct 2019The continuous crosstalk between microglia and neurons is required for microglia housekeeping functions and contributes to brain homeostasis. Through these exchanges,... (Review)
Review
The continuous crosstalk between microglia and neurons is required for microglia housekeeping functions and contributes to brain homeostasis. Through these exchanges, microglia take part in crucial brain functions, including development and plasticity. The alteration of neuron-microglia communication contributes to brain disease states with consequences, ranging from synaptic function to neuronal survival. This review focuses on the signaling pathways responsible for neuron-microglia crosstalk, highlighting their physiological roles and their alteration or specific involvement in disease. In particular, we discuss studies, establishing how these signaling allow microglial cells to control relevant physiological functions during brain development, including synaptic formation and circuit refinement. In addition, we highlight how microglia and neurons interact functionally to regulate highly dynamical synaptic functions. Microglia are able to release several signaling molecules involved in the regulation of synaptic activity and plasticity. On the other side, molecules of neuronal origin control microglial processes motility in an activity-dependent manner. Indeed, the continuous crosstalk between microglia and neurons is required for the sensing and housekeeping functions of microglia and contributes to the maintenance of brain homeostasis and, particularly, to the sculpting of neuronal connections during development. These interactions lay on the delicate edge between physiological processes and homeostasis alteration in pathology and are themselves altered during neuroinflammation. The full description of these processes could be fundamental for understanding brain functioning in health and disease.
Topics: Animals; Humans; Microglia; Neurons; Signal Transduction
PubMed: 31112798
DOI: 10.1016/j.semcdb.2019.05.017 -
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 -
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 -
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