Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(11), P. 2472 - 2488

Published: Aug. 19, 2021

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist a vacuum. Instead, pre- postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise four elements of contemporary tetrapartite synapse model. While research this area is still just beginning, accumulating evidence points toward novel role for microglia regulating ECM during normal brain homeostasis, such processes may, turn, become dysfunctional disease. As it relates to synapses, reported modify perisynaptic matrix, diffuse that surrounds dendritic axonal terminals, as well perineuronal nets (PNNs), specialized reticular formations compact enwrap neuronal subsets stabilize proximal synapses. The interconnected relationship between they embedded suggests alterations one structure necessarily affect dynamics other, may need sculpt within. Here, we provide an overview microglial regulation PNNs, propose candidate mechanisms these structures be modified, present implications modifications homeostasis

Language: Английский

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Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy

Science Advances, Journal Year: 2023, Volume and Issue: 9(21)

Published: May 26, 2023

Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, long-term cognitive dysfunction. We identified microglia C1q complement activation in hippocampal autopsy tissue patients with increased C1q-mediated synaptic pruning murine polymicrobial model. Unbiased transcriptomics isolated derived from septic mice revealed an involvement the innate immune system, activation, up-regulation lysosomal pathways during SAE parallel to neuronal damage. Microglial engulfment C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection specific C1q-blocking antibody. Pharmacologically targeting PLX5622, CSF1-R inhibitor, reduced levels number synapses, protected damage synapse loss, improved neurocognitive outcome. Thus, we complement-dependent as crucial pathomechanism for development defects SAE.

Language: Английский

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Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes

Autophagy, Journal Year: 2023, Volume and Issue: 19(7), P. 2026 - 2044

Published: Jan. 18, 2023

Excessive and prolonged neuroinflammation following traumatic brain injury (TBI) contributes to long-term tissue damage poor functional outcomes. However, the mechanisms contributing exacerbated inflammatory responses after remain poorly understood. Our previous work showed that macroautophagy/autophagy flux is inhibited in neurons TBI mice neuronal cell death. In present study, we demonstrate autophagy also activated microglia infiltrating macrophages, this potentiates injury-induced neuroinflammatory responses. Macrophage/microglia-specific knockout of essential gene Becn1 led overall increase TBI. particular, observed excessive activation innate immune responses, including both type-I interferon inflammasome pathways. Defects microglial macrophage were associated with decreased phagocytic clearance danger/damage-associated molecular patterns (DAMP) responsible for cellular data demonstrated a role precision targeting degradation pathways components, such as NLRP3 inflammasome. Finally, inhibition microglial/macrophage increased neurodegeneration worse cognitive outcomes Conversely, increasing by treatment rapamycin inflammation improved wild-type Overall, our demonstrates macrophages long term may prevent resolution regeneration.Abbreviations:Becn1/BECN1, beclin 1, related; CCI, controlled cortical impact; Cybb/CYBB/NOX2: cytochrome b-245, beta polypeptide; DAMP, patterns; Il1b/IL1B/Il-1β, interleukin 1 beta; LAP, LC3-associated phagocytosis; Map1lc3b/MAP1LC3/LC3, microtubule-associated protein light chain 3 Mefv/MEFV/TRIM20: Mediterranean fever; Nos2/NOS2/iNOS: nitric oxide synthase 2, inducible; Nlrp3/NLRP3, NLR family, pyrin domain containing 3; Sqstm1/SQSTM1/p62, sequestosome 1; TBI, injury; Tnf/TNF/TNF-α, tumor necrosis factor; Ulk1/ULK1, unc-51 like kinase 1.

Language: Английский

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Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: March 7, 2023

Microglia are the principal resident immune cells in central nervous system (CNS) and play important roles development of CNS disorders. In recent years, there have been significant developments our understanding microglia, we now greater insight into temporal spatial patterns microglia activation a variety disorders, as well interactions between neurons. A signaling pathways implicated. However, to date, all published clinical trials failed demonstrate efficacy over placebo. This review summarizes results studies attempts provide mechanistic view activation, inflammation, tissue repair,

Language: Английский

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Reactive gliosis in traumatic brain injury: a comprehensive review

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 28, 2024

Traumatic brain injury (TBI) is one of the most common pathological conditions impacting central nervous system (CNS). A neurological deficit associated with TBI results from a complex pathogenetic mechanisms including glutamate excitotoxicity, inflammation, demyelination, programmed cell death, or development edema. The critical components contributing to CNS response, damage control, and regeneration after are glial cells–in reaction tissue damage, their activation, hypertrophy, proliferation occur, followed by formation scar. scar creates barrier in damaged helps protect acute phase post-injury. However, this process prevents complete recovery late/chronic producing permanent scarring, which significantly impacts function. Various types participate formation, but mostly attributed reactive astrocytes microglia, play important roles several pathologies. Novel technologies whole-genome transcriptomic epigenomic analyses, unbiased proteomics, show that both microglia represent groups heterogenic subpopulations different genomic functional characteristics, responsible for role neurodegeneration, neuroprotection regeneration. Depending on representation distinct glia subpopulations, as well regenerative processes delayed neurodegeneration may thus differ nearby remote areas structures. This review summarizes process, where resultant effect severity-, region- time-dependent determined model distance explored area lesion site. Here, we also discuss findings concerning intercellular signaling, long-term possibilities novel therapeutical approaches. We believe comprehensive study an emphasis cells, involved post-injury processes, be helpful further research decisive factor when choosing model.

Language: Английский

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Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 13101 - 13101

Published: Dec. 3, 2021

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region brain. Stroke is leading cause death and common disability, with over 17 million people worldwide suffering from each year. It now well-documented that neuroinflammation immune mediators play key role acute long-term neuronal tissue damage healing, not only infarct core but also distal regions. Importantly, these regions, termed sites secondary neurodegeneration (SND), spikes may be seen sometime after initial onset, prior presence within However, it acknowledge that, despite mounting information describing following ischaemic stroke, exact mechanisms whereby inflammatory cells their drive stroke-induced are still fully understood. As result, current anti-inflammatory treatments have failed show efficacy clinical trials. In this review we discuss complexities post-stroke neuroinflammation, specifically how affects outcome acutely, chronically, SND. We then previously assessed therapies, particular focus on anti-inflammatories repurposed target SND-associated neuroinflammation.

Language: Английский

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The role of innate immunity in Alzheimer's disease

Immunological Reviews, Journal Year: 2020, Volume and Issue: 297(1), P. 225 - 246

Published: June 26, 2020

Abstract The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hinges on the predominant clinical role of beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment AD. Recent AD field identified brain‐resident macrophages, known as microglia, their receptors integral regulators both initiation propagation inflammation, Aβ accumulation, neuronal loss, memory decline Emerging studies have also begun to reveal critical roles distinct innate immune pathways pathogenesis, which led great interest harnessing response a therapeutic strategy treat In this review, we will highlight recent advancements our understanding immunity inflammation onset progression. Additionally, there been mounting evidence suggesting pivotal contributions environmental factors lifestyle choices pathogenesis. Therefore, discuss findings, that many these risk influence progression via modulation microglia responses.

Language: Английский

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Gut microbial dysbiosis after traumatic brain injury modulates the immune response and impairs neurogenesis

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: March 10, 2021

Abstract The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap paramount clinical significance as TBI patients are highly susceptible to alterations in by antibiotic exposure. Antibiotic-induced microbial dysbiosis established prior significantly worsened neuronal loss and reduced microglia activation injured hippocampus with concomitant changes fear memory response. Importantly, exposure for 1 week after cortical infiltration Ly6C high monocytes, increased microglial pro-inflammatory markers, decreased T lymphocyte infiltration, which persisted through month post-injury. Moreover, was associated neurogenesis dentate gyrus TBI. By 3 months (11 weeks discontinuation antibiotics), we observed proliferation, hippocampal loss, modulation These data demonstrate that antibiotic-induced impacts neuroinflammation, neurogenesis, implicate a potential therapeutic intervention

Language: Английский

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Microglia-mediated neuroinflammation and neuroplasticity after stroke

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Aug. 16, 2022

Stroke remains a major cause of long-term disability and mortality worldwide. The immune system plays an important role in determining the condition brain following stroke. As resident innate cells central nervous system, microglia are primary responders defense network covering entire parenchyma, exert various functions depending on dynamic communications with neurons, astrocytes, other neighboring under both physiological or pathological conditions. Microglia activation polarization is crucial for damage repair ischemic stroke, considered double-edged sword neurological recovery. can exist pro-inflammatory states promote secondary damage, but they also secrete anti-inflammatory cytokines neurotrophic factors facilitate recovery In this review, we focus mechanisms microglia-mediated neuroinflammation neuroplasticity after ischemia relevant potential microglia-based interventions stroke therapy.

Language: Английский

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Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 22, 2022

Traumatic brain injury (TBI) is associated with high mortality and disability, a substantial socioeconomic burden. With the standardization of treatment process, there increasing interest in role that secondary insult TBI plays outcome heterogeneity. The neither detrimental nor beneficial an absolute sense, among which inflammatory response was complex cascade events can thus be regarded as double-edged sword. Therefore, clinicians should take generation balance neuroinflammation following seriously. In this review, we summarize current human animal model studies provide better understanding different stages TBI. particular, advances using proteomic transcriptomic techniques have enabled us to identify functional specific delineation immune cell patients. Based on recent our activation, present difference between diffuse axonal focal injury. addition, give figurative profiling general paradigm pre- post-injury settings employing bow-tie framework.

Language: Английский

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