scholarly journals Effects of Cocaine on Human Glial-Derived Extracellular Vesicles

2021 ◽  
Vol 8 ◽  
Author(s):  
Sanjay Kumar ◽  
Qiana L. Matthews ◽  
Brian Sims
Keyword(s):  
Extracellular Vesicles ◽  
Cell Activation ◽  
Microglial Cell ◽  
Drugs Of Abuse ◽  
Inflammatory Responses ◽  
Cell Communication ◽  
Brain Parenchyma ◽  
Cocaine Exposure ◽  
Apoptotic Marker ◽  
The Central Nervous System

BackgroundMicroglia are important myeloid cells present in the brain parenchyma that serve a surveillance function in the central nervous system. Microglial cell activation results in neuroinflammation that, when prolonged, can disrupt immune homeostasis and neurogenesis. Activated microglia-derived extracellular vesicles (EVs) may be involved in the propagation of inflammatory responses and modulation of cell-to-cell communication. However, a complete understanding of how EVs are regulated by drugs of abuse, such as cocaine, is still lacking.FindingsCocaine exposure reduced human microglial cell (HMC3) viability, decreased expression of CD63 and dectin-1 in HMC3-derived EVs, and increased expression of the apoptotic marker histone H2A.x in HMC3-derived EVs.ConclusionCocaine impacts HMC3 cell viability and specific EV protein expression, which could disrupt cellular signaling and cell-to-cell communication.

Microglia extracellular vesicles: focus on molecular composition and biological function

2021 ◽  
Vol 49 (4) ◽  
pp. 1779-1790 ◽  
Author(s):  
Lorenzo Ceccarelli ◽  
Chiara Giacomelli ◽  
Laura Marchetti ◽  
Claudia Martini
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Biological Effects ◽  
Genetic Material ◽  
Cell Communication ◽  
Molecular Composition ◽  
Cargo Proteins ◽  
A Cell ◽  
The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

scholarly journals Mitochondrial Extracellular Vesicles – Origins and Roles

2021 ◽  
Vol 14 ◽  
Author(s):  
Lydia Amari ◽  
Marc Germain
Keyword(s):  
Reactive Oxygen Species ◽  
Extracellular Vesicles ◽  
Large Range ◽  
Inflammatory Responses ◽  
Cell Communication ◽  
Oxygen Species ◽  
Mitochondrial Content ◽  
Communication Devices ◽  
Metabolic Reactions ◽  
Cellular Compartments

Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Within cells, mitochondria are responsible for a large range of metabolic reactions, but they can also produce damaging levels of reactive oxygen species and induce inflammation when damaged. Consistent with this, recent evidence suggests that EV-mediated transfer of mitochondrial content alters metabolic and inflammatory responses of recipient cells. As EV mitochondrial content is also altered in some pathologies, this could have important implications for their diagnosis and treatment. In this review, we will discuss the nature and roles of mitochondrial EVs, with a special emphasis on the nervous system.

scholarly journals Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1327 ◽  
Author(s):  
Loredana Leggio ◽  
Greta Paternò ◽  
Silvia Vivarelli ◽  
Francesca L’Episcopo ◽  
Cataldo Tirolo ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cell Communication ◽  
Bioactive Molecules ◽  
Substantia Nigra Pars Compacta ◽  
Diagnostic Tools ◽  
Target Cells ◽  
Small Interfering Rnas ◽  
Wide Range ◽  
Ligand Interactions ◽  
The Central Nervous System

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

scholarly journals TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2145 ◽  
Author(s):  
Stefano Raffaele ◽  
Marta Lombardi ◽  
Claudia Verderio ◽  
Marta Fumagalli
Keyword(s):  
Extracellular Vesicles ◽  
Cell Communication ◽  
Neuroinflammatory Response ◽  
Brain Functions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies ◽  
Circuit Formation ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.

scholarly journals Molecular Characterization of Temozolomide-Treated and Non Temozolomide-Treated Glioblastoma Cells Released Extracellular Vesicles and Their Role in the Macrophage Response

2020 ◽  
Vol 21 (21) ◽  
pp. 8353
Author(s):  
Elisa Panzarini ◽  
Stefano Tacconi ◽  
Elisabetta Carata ◽  
Stefania Mariano ◽  
Ada Maria Tata ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Extracellular Vesicles ◽  
Cell Activation ◽  
Cell Communication ◽  
Molecular Profile ◽  
Surface Markers ◽  
Macrophage Response ◽  
A Cell ◽  
Potential Biomarkers

Extracellular vesicles (EVs) are widely investigated in glioblastoma multiforme (GBM) for their involvement in regulating GBM pathobiology as well as for their use as potential biomarkers. EVs, through cell-to-cell communication, can deliver proteins, nucleic acids, and lipids that are able to reprogram tumor-associated macrophages (TAMs). This research is aimed to concentrate, characterize, and identify molecular markers of EVs subtypes released by temozolomide (TMZ)-treated and non TMZ-treated four diverse GBM cells. Morphology, size distribution, and quantity of small (sEVs) and large (lEVs) vesicles were analyzed by cryo-TEM. Quality and quantity of EVs surface markers were evaluated, having been obtained by Western blotting. GBM cells shed a large amount of EVs, showing a cell line dependent molecular profile A comparative analysis distinguished sEVs and lEVs released by temozolomide (TMZ)-treated and non TMZ-treated GBM cells on the basis of quantity, size and markers expression. Finally, the GBM-derived sEVs and lEVs, irrespective of TMZ treatment, when challenged with macrophages, modulated cell activation toward a tendentially M2b-like phenotype.

scholarly journals Apolipoprotein E4 expressed by microglia impairs microglial functions and enhances neurotoxicity

2020 ◽  
Author(s):  
Na Wang ◽  
Min Wei ◽  
Xinxiu Li ◽  
Lin Jia ◽  
Jianguo Li ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Biological Effects ◽  
Brain Parenchyma ◽  
Apoe Isoforms ◽  
Major Cell Type ◽  
The Central Nervous System ◽  
Ε4 Allele ◽  
The Brain

Abstract Background Microglia, the major cell type that mediates active immune defence in the central nervous system (CNS), constantly survey the brain parenchyma through highly motile processes. Mounting evidence has implicated both beneficial and toxic roles of microglia when over-activated upon neuronal injury. Understanding the function of microglia in the brain may uncover the regulatory mechanisms for neuroinflammation and facilitate the development of a novel therapeutic strategy for Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE) is a major genetic risk factor for the late onset AD. ApoE, as the major cholesterol carrier in the brain, has been implicated in AD pathogenesis. However, how APOE and APOE isoforms directly regulate microglial functions remains largely unknown. Methods Using primary culture of microglia from Apoe knockout (KO) mice, APOE3 and APOE4 targeted replacement (TR) mouse, we investigated the characteristics of microglial secreted apoE particles and the biological effects of apoE isoforms on microglial inflammatory response, migratory ability, cell viability and proliferation. Meanwhile, microglia-neuron co-culture system was utilized to study the effects of apoE isoforms on neurite outgrowth.Results Herein, we found that microglia secret abundant lipidated apoE. Interestingly, apoE4 particles from primary microglia exhibited a higher lipidation status compared to apoE3 particles. Furthermore, apoE4 microglia exhibited a reduced migratory ability as well as enhanced inflammatory responses and neurotoxicity, indicating microglial apoE4 is involved in unfavourable functions. Conclusions Our findings revealed the critical roles for apoE and apoE isoforms in regulating microglial functions. Our results also indicate that targeting apoE-mediated microglial inflammatory responses may serve as a potential therapeutic strategy for AD.

scholarly journals Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic

2021 ◽  
Vol 15 ◽  
Author(s):  
Elisa Gonçalves de Andrade ◽  
Eva Šimončičová ◽  
Micaël Carrier ◽  
Haley A. Vecchiarelli ◽  
Marie-Ève Robert ◽  
...  
Keyword(s):  
Mental Health ◽  
Central Nervous System ◽  
Nervous System ◽  
Inflammatory Responses ◽  
Psychiatric Symptoms ◽  
Brain Parenchyma ◽  
Molecular Signature ◽  
The Central Nervous System ◽  
Psychiatric Manifestations ◽  
The Brain

Coronavirus disease 2019 (COVID-19) is marked by cardio-respiratory alterations, with increasing reports also indicating neurological and psychiatric symptoms in infected individuals. During COVID-19 pathology, the central nervous system (CNS) is possibly affected by direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion, exaggerated systemic inflammatory responses, or hypoxia. Psychosocial stress imposed by the pandemic further affects the CNS of COVID-19 patients, but also the non-infected population, potentially contributing to the emergence or exacerbation of various neurological or mental health disorders. Microglia are central players of the CNS homeostasis maintenance and inflammatory response that exert their crucial functions in coordination with other CNS cells. During homeostatic challenges to the brain parenchyma, microglia modify their density, morphology, and molecular signature, resulting in the adjustment of their functions. In this review, we discuss how microglia may be involved in the neuroprotective and neurotoxic responses against CNS insults deriving from COVID-19. We examine how these responses may explain, at least partially, the neurological and psychiatric manifestations reported in COVID-19 patients and the general population. Furthermore, we consider how microglia might contribute to increased CNS vulnerability in certain groups, such as aged individuals and people with pre-existing conditions.

scholarly journals Neuroinflammation: A Potential Risk for Dementia

2022 ◽  
Vol 23 (2) ◽  
pp. 616
Author(s):  
Md Afroz Ahmad ◽  
Ozaifa Kareem ◽  
Mohammad Khushtar ◽  
Md Akbar ◽  
Md Rafiul Haque ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cell Activation ◽  
Microglial Cell ◽  
Oxygen Species ◽  
Independent Function ◽  
Published Evidence ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
The Brain

Dementia is a neurodegenerative condition that is considered a major factor contributing to cognitive decline that reduces independent function. Pathophysiological pathways are not well defined for neurodegenerative diseases such as dementia; however, published evidence has shown the role of numerous inflammatory processes in the brain contributing toward their pathology. Microglia of the central nervous system (CNS) are the principal components of the brain’s immune defence system and can detect harmful or external pathogens. When stimulated, the cells trigger neuroinflammatory responses by releasing proinflammatory chemokines, cytokines, reactive oxygen species, and nitrogen species in order to preserve the cell’s microenvironment. These proinflammatory markers include cytokines such as IL-1, IL-6, and TNFα chemokines such as CCR3 and CCL2 and CCR5. Microglial cells may produce a prolonged inflammatory response that, in some circumstances, is indicated in the promotion of neurodegenerative diseases. The present review is focused on the involvement of microglial cell activation throughout neurodegenerative conditions and the link between neuroinflammatory processes and dementia.

scholarly journals Glioma-derived extracellular vesicles promote tumor progression by conveying WT1

2020 ◽  
Vol 41 (9) ◽  
pp. 1238-1245
Author(s):  
Taishi Tsutsui ◽  
Hironori Kawahara ◽  
Ryouken Kimura ◽  
Yu Dong ◽  
Shabierjiang Jiapaer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Progression ◽  
Communication Networks ◽  
Extracellular Vesicles ◽  
Wilms Tumor ◽  
Cell Communication ◽  
Negative Regulator ◽  
Primary Tumors ◽  
Model Mouse ◽  
The Central Nervous System

Abstract Glioma persists as one of the most aggressive primary tumors of the central nervous system. Glioma cells are known to communicate with tumor-associated macrophages/microglia via various cytokines to establish the tumor microenvironment. However, how extracellular vesicles (EVs), emerging regulators of cell–cell communication networks, function in this process is still elusive. We report here that glioma-derived EVs promote tumor progression by affecting microglial gene expression in an intracranial implantation glioma model mouse. The gene expression of thrombospondin-1 (Thbs1), a negative regulator of angiogenesis, was commonly downregulated in microglia after the addition of EVs isolated from different glioma cell lines, which endogenously expressed Wilms tumor-1 (WT1). Conversely, WT1-deficiency in the glioma-derived EVs significantly attenuated the Thbs1 downregulation and suppressed the tumor progression. WT1 was highly expressed in EVs obtained from the cerebrospinal fluid of human patients with malignant glioma. Our findings establish a novel model of tumor progression via EV-mediated WT1–Thbs1 intercellular regulatory pathway, which may be a future diagnostic or therapeutic target.

scholarly journals Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain

2014 ◽  
Vol 369 (1652) ◽  
pp. 20130516 ◽  
Author(s):  
D. M. Pegtel ◽  
L. Peferoen ◽  
S. Amor
Keyword(s):  
Extracellular Vesicles ◽  
Messenger Rna ◽  
Potential Role ◽  
Cell Communication ◽  
Extracellular Rna ◽  
Anti Cancer ◽  
The Status ◽  
The Central Nervous System ◽  
Stressed Cells

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by ‘infecting’ neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS.

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