scholarly journals Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Simone Bido ◽  
Sharon Muggeo ◽  
Luca Massimino ◽  
Matteo Jacopo Marzi ◽  
Serena Gea Giannelli ◽  
...  
Keyword(s):  
Immune Cells ◽  
Neuronal Degeneration ◽  
Brain Parenchyma ◽  
Microglial Cells ◽  
Dopaminergic Neurodegeneration ◽  
Progressive Degeneration ◽  
Toxic Environment ◽  
Inflammatory State ◽  
Peripheral Immune Cells ◽  
The Brain

AbstractRecent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.

scholarly journals Aquaporin-4 Expression during Toxic and Autoimmune Demyelination

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2187
Author(s):  
Sven Olaf Rohr ◽  
Theresa Greiner ◽  
Sarah Joost ◽  
Sandra Amor ◽  
Paul van der Valk ◽  
...  
Keyword(s):  
Immune Cells ◽  
Water Channel ◽  
Staining Intensity ◽  
Brain Parenchyma ◽  
Aquaporin 4 ◽  
Aqp4 Expression ◽  
Humoral Immune ◽  
Autoimmune Demyelination ◽  
Peripheral Immune Cells ◽  
The Brain

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood–brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

scholarly journals Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 957
Author(s):  
Brad T. Casali ◽  
Erin G. Reed-Geaghan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cells ◽  
Expression Patterns ◽  
Brain Parenchyma ◽  
Primary Role ◽  
And Function ◽  
Inflammatory Milieu ◽  
The Brain ◽  
Homeostatic State

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

Exploration of beneficial and deleterious effects of inflammation in stroke: dynamics of inflammation cells

2009 ◽  
Vol 367 (1908) ◽  
pp. 4699-4716 ◽  
Author(s):  
Taïssia Lelekov-Boissard ◽  
Guillemette Chapuisat ◽  
Jean-Pierre Boissel ◽  
Emmanuel Grenier ◽  
Marie-Aimée Dronne
Keyword(s):  
Immune Cells ◽  
Blood Cells ◽  
Inflammatory Process ◽  
Living Cells ◽  
Therapeutic Strategies ◽  
Brain Parenchyma ◽  
Brain Cell ◽  
Cytokines And Chemokines ◽  
The Brain

The inflammatory process during stroke consists of activation of resident brain microglia and recruitment of leucocytes, namely neutrophils and monocytes/macrophages. During inflammation, microglial cells, neutrophils and macrophages secrete inflammatory cytokines and chemokines, and phagocytize dead cells. The recruitment of blood cells (neutrophils and macrophages) is mediated by the leucocyte–endothelium interactions and more specifically by cell adhesion molecules. A mathematical model is proposed to represent the dynamics of various brain cells and of immune cells (neutrophils and macrophages). This model is based on a set of six ordinary differential equations and explores the beneficial and deleterious effects of inflammation, respectively phagocytosis by immune cells and the release of pro-inflammatory mediators and nitric oxide (NO). The results of our simulations are qualitatively consistent with those observed in experiments in vivo and would suggest that the increase of phagocytosis could contribute to the increase of the percentage of living cells. The inhibition of the production of cytokines and NO and the blocking of neutrophil and macrophage infiltration into the brain parenchyma led also to the improvement of brain cell survival. This approach may help to explore the respective contributions of the beneficial and deleterious roles of the inflammatory process in stroke, and to study various therapeutic strategies in order to reduce stroke damage.

scholarly journals Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

2021 ◽  
Author(s):  
Dilidaer Misilimu ◽  
Wei Li ◽  
Di Chen ◽  
Pengju Wei ◽  
Yichen Huang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Immune Cells ◽  
Intranasal Administration ◽  
Neurological Function ◽  
Salvinorin A ◽  
Stroke Model ◽  
Peripheral Immune Cells ◽  
The Brain

AbstractSalvinorin A (SA), a highly selective kappa opioid receptor agonist, has been shown to reduce brain infarct volume and improve neurological function after ischemic stroke. However, the underlying mechanisms have not been fully understood yet. Therefore, we explored whether SA provides neuroprotective effects by regulating the immune response after ischemic stroke both in the central nervous system (CNS) and peripheral circulation. In this study, adult male mice were subjected to transient Middle Cerebral Artery Occlusion (tMCAO) and then were treated intranasally with SA (50 μg/kg) or with the vehicle dimethyl sulfoxide (DMSO). Multiple behavioral tests were used to evaluate neurofunction. Flow cytometry and immunofluorescence staining were used to evaluate the infiltration of peripheral immune cells into the brain. The tracer cadaverine and endogenous immunoglobulin G (IgG) extravasation were used to detect blood brain barrier leakage. We observed that SA intranasal administration after ischemic stroke decreased the expression of pro-inflammatory factors in the brain. SA promoted the polarization of microglia/macrophages into a transitional phenotype and decreased the pro-inflammatory phenotype in the brain after tMCAO. Interestingly, SA treatment scarcely altered the number of peripheral immune cells but decreased the macrophage and neutrophil infiltration into the brain at 24 h after tMCAO. Furthermore, SA treatment also preserved BBB integrity, reduced long-term brain atrophy and white matter injury, as well as improved the long-term neurofunctional outcome in mice. In this study, intranasal administration of SA improved long-term neurological function via immuno-modulation and by preserving blood–brain barrier integrity in a mouse ischemic stroke model, suggesting that SA could potentially serve as an alternative treatment strategy for ischemic stroke. Graphic Abstract

scholarly journals Immune cells and CNS physiology: Microglia and beyond

2018 ◽  
Vol 216 (1) ◽  
pp. 60-70 ◽  
Author(s):  
Geoffrey T. Norris ◽  
Jonathan Kipnis
Keyword(s):  
Central Nervous System ◽  
Immune Cells ◽  
Brain Function ◽  
Brain Parenchyma ◽  
The Body ◽  
Immune Repertoire ◽  
Perivascular Macrophages ◽  
The Central Nervous System ◽  
Cns Immunity ◽  
The Brain

Recent advances have directed our knowledge of the immune system from a narrative of “self” versus “nonself” to one in which immune function is critical for homeostasis of organs throughout the body. This is also the case with respect to the central nervous system (CNS). CNS immunity exists in a segregated state, with a marked partition occurring between the brain parenchyma and meningeal spaces. While the brain parenchyma is patrolled by perivascular macrophages and microglia, the meningeal spaces are supplied with a diverse immune repertoire. In this review, we posit that such partition allows for neuro–immune crosstalk to be properly tuned. Convention may imply that meningeal immunity is an ominous threat to brain function; however, recent studies have shown that its presence may instead be a steady hand directing the CNS to optimal performance.

scholarly journals Invasion of Peripheral Immune Cells into Brain Parenchyma after Cardiac Arrest and Resuscitation

2018 ◽  
Vol 9 (3) ◽  
pp. 412 ◽  
Author(s):  
Can Zhang ◽  
Nicole R. Brandon ◽  
Kerryann Koper ◽  
Pei Tang ◽  
Yan Xu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Immune Cells ◽  
Brain Parenchyma ◽  
Peripheral Immune Cells

scholarly journals Physiology of Microglia

2011 ◽  
Vol 91 (2) ◽  
pp. 461-553 ◽  
Author(s):  
Helmut Kettenmann ◽  
Uwe-Karsten Hanisch ◽  
Mami Noda ◽  
Alexei Verkhratsky
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Brain Parenchyma ◽  
Microglial Cells ◽  
Activation Process ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cellular Compartments ◽  
The Brain

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

scholarly journals CHANGES IN THE CONTENT OF IMMUNE CELLS CONTAINING THE FcR III RECEPTOR IN THE SLEEP AND BRAIN AFTER EXPERIMENTAL TBI

2020 ◽  
pp. 60-65
Author(s):  
Микола Лісяний ◽  
Настя Паламарьова ◽  
Людмила Бєльська ◽  
Антоніна Потапова
Keyword(s):  
Immune Cells ◽  
Craniocerebral Trauma ◽  
Brain Parenchyma ◽  
Immunomodulatory Activity ◽  
Left And Right ◽  
Immunomodulatory Drug ◽  
Immunomodulatory Properties ◽  
Low Levels ◽  
The Brain

At TBI there are disturbances in activity of immune system, can complicate regenerative and reparative responses in a brain. The aim of the study was to study the content of CD-16 cells in the spleen and brain parenchyma at different times after TBI in rats and in the correction of disorders in their composition by immunomodulatory drug galalite.Methods. Craniocerebral trauma in animals was modeled by dropping a load weighing 100 g from a height of 120 cm on the head of rats that were anesthetized and were in a state of narcotic sleep, which lasted up to 30 minutes. To correct the resulting disorders used immunomodulatory drug galavit at a dose of 2 mg / kg of animal weight in a volume of0.5 ml, which was administered intramuscularly to animals for 2, 3, 4 days after injury. The spleen and the left and right hemispheres of the brain were homogenized in 5.0 ml of medium 199 and suspensions containing 10.0x106 cells per 1 ml of medium 199 microglia were prepared and infiltrated CNS monocytes were prepared by the method of Sedgwick J. in co-authors. Determination of the level of CD-16 cells in suspensions of spleen and microglia was performed on a flow cytometer using monoclonal antibodies against CD-16 receptor company BD Biosciences according to the instructions for antibodies.Results. In mild TBI in rats, the number of CD- 16 cells containing the FcR III receptor decreases in the spleen for 2 to 5 days, and the number of these cells in the fractions of microglial cells increases. Galavit is a drug with immunomodulatory properties, has virtually no effect on low levels of CD-16 cells in the spleen and stimulates their accumulation in the brain for 10 days after TBI.Conclusions. The results indicate the effect of Galavit on the level of CD-16 cells in the spleen and brain, which indicates the immunomodulatory activity of this drug.

Natural Terpenoids as Neuroinflammatory Inhibitors in LPS-stimulated BV-2 Microglia

2019 ◽  
Vol 19 ◽  
Author(s):  
Yuanzhen Xu ◽  
Hongbo Wei ◽  
Jinming Gao
Keyword(s):  
Alzheimer’S Disease ◽  
Neurodegenerative Diseases ◽  
Immune Cells ◽  
Natural Compounds ◽  
Typical Feature ◽  
Brain Inflammation ◽  
Bacterial Lipopolysaccharide ◽  
Microglial Cells ◽  
Diverse Group ◽  
The Brain

Background: Neuroinflammation is a typical feature of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Microglia, the resident immune cells of the brain, readily become activated in response to infection or injury. Uncontrolled and overactivated microglia can release pro-inflammatory and cytotoxic factors and are the major culprit in neuroinflammation. Hence, research into novel neuroinflammatory inhibitors is of paramount importance for the treatment of neurodegenerative diseases. Bacterial lipopolysaccharide, widely used in studies of brain inflammation, initiates several major cellular activities that critically contribute to the pathogenesis of neuroinflammation. Objective: This review will highlight the progress on terpenoids, an important and structurally diverse group of natural compounds, as neuroinflammatory inhibitors in lipopolysaccharide-stimulated BV-2 microglial cells over the last 20 years.

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