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Editorial

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3 pages, 195 KiB

Open AccessEditorial

The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses

by Ruqayya Afridi, Makoto Tsuda, Hoon Ryu and Kyoungho Suk

Cells 2022, 11(4), 659; https://doi.org/10.3390/cells11040659 - 14 Feb 2022

Cited by 6 | Viewed by 2731

Abstract

The historical concept of glia just as the glue of brain tissue has been challenged by the accumulation of concrete evidence showing the multifunctional role of these cells during development and in the adult brain [...] Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

Research

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16 pages, 4855 KiB

Open AccessArticle

High-Throughput Analysis of Astrocyte Cultures Shows Prevention of Reactive Astrogliosis by the Multi-Nutrient Combination Fortasyn Connect

by Aina Badia-Soteras, Janneke de Vries, Werner Dykstra, Laus M. Broersen, Jan Martin Verkuyl, August B. Smit and Mark H. G. Verheijen

Cells 2022, 11(9), 1428; https://doi.org/10.3390/cells11091428 - 22 Apr 2022

Cited by 6 | Viewed by 3017

Abstract

Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is [...] Read more.

Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is apparent in many neurodegenerative diseases, among which one is Alzheimer’s disease (AD). Recent clinical trials on early-stage AD have demonstrated that Fortasyn Connect (FC), a multi-nutrient combination providing specific precursors and cofactors for phospholipid synthesis, helps to maintain neuronal functional connectivity and cognitive performance of patients. Several studies have shown that FC may act through its effects on neuronal survival and synaptogenesis, leading to reduced astrocyte reactivity, but whether FC can directly counteract astrocyte reactivity remains to be elucidated. Hence, we developed an in vitro model of reactive astrogliosis using the pro-inflammatory cytokines TNF-α and IFN-γ together with an automated high-throughput assay (AstroScan) to quantify molecular and morphological changes that accompany reactive astrogliosis. Next, we showed that FC is potent in preventing cytokine-induced reactive astrogliosis, a finding that might be of high relevance to understand the beneficial effects of FC-based interventions in the context of neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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18 pages, 3051 KiB

Open AccessArticle

Morphological and Calcium Signaling Alterations of Neuroglial Cells in Cerebellar Cortical Dysplasia Induced by Carmustine

by Cynthia Alejandra Rodríguez-Arzate, Marianne Lizeth Martínez-Mendoza, Israel Rocha-Mendoza, Yryx Luna-Palacios, Jacob Licea-Rodríguez and Ataúlfo Martínez-Torres

Cells 2021, 10(7), 1581; https://doi.org/10.3390/cells10071581 - 23 Jun 2021

Cited by 3 | Viewed by 2740

Abstract

Cortical dysplasias are alterations in the organization of the layers of the brain cortex due to problems in neuronal migration during development. The neuronal component has been widely studied in experimental models of cortical dysplasias. In contrast, little is known about how glia [...] Read more.

Cortical dysplasias are alterations in the organization of the layers of the brain cortex due to problems in neuronal migration during development. The neuronal component has been widely studied in experimental models of cortical dysplasias. In contrast, little is known about how glia are affected. In the cerebellum, Bergmann glia (BG) are essential for neuronal migration during development, and in adult they mediate the control of fine movements through glutamatergic transmission. The aim of this study was to characterize the morphology and intracellular calcium dynamics of BG and astrocytes from mouse cerebellum and their modifications in a model of cortical dysplasia induced by carmustine (BCNU). Carmustine-treated mice were affected in their motor coordination and balance. Cerebellar dysplasias and heterotopias were more frequently found in lobule X. Morphology of BG cells and astrocytes was affected, as were their spontaneous [Ca²⁺]ⁱ transients in slice preparation and in vitro. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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17 pages, 2946 KiB

Open AccessArticle

Cell Surface Profiling of Retinal Müller Glial Cells Reveals Association to Immune Pathways after LPS Stimulation

by Lea Lorenz, Sieglinde Hirmer, Adrian Schmalen, Stefanie M. Hauck and Cornelia A. Deeg

Cells 2021, 10(3), 711; https://doi.org/10.3390/cells10030711 - 23 Mar 2021

Cited by 15 | Viewed by 3095

Abstract

Retinal Müller glial cells (RMG) are involved in virtually every retinal disease; however, the role of these glial cells in neuroinflammation is still poorly understood. Since cell surface proteins play a decisive role in immune system signaling pathways, this study aimed at characterizing [...] Read more.

Retinal Müller glial cells (RMG) are involved in virtually every retinal disease; however, the role of these glial cells in neuroinflammation is still poorly understood. Since cell surface proteins play a decisive role in immune system signaling pathways, this study aimed at characterizing the changes of the cell surface proteome of RMG after incubation with prototype immune system stimulant lipopolysaccharide (LPS). While mass spectrometric analysis of the human Müller glia cell line MIO-M1 revealed 507 cell surface proteins in total, with 18 proteins significantly more abundant after stimulation (ratio ≥ 2), the surfaceome of primary RMG comprised 1425 proteins, among them 79 proteins with significantly higher abundance in the stimulated state. Pathway analysis revealed notable association with immune system pathways such as “antigen presentation”, “immunoregulatory interactions between a lymphoid and a non-lymphoid cell” and “cell migration”. We could demonstrate a higher abundance of proteins that are usually ascribed to antigen-presenting cells (APCs) and function to interact with T-cells, suggesting that activated RMG might act as atypical APCs in the course of ocular neuroinflammation. Our data provide a detailed description of the unstimulated and stimulated RMG surfaceome and offer fundamental insights regarding the capacity of RMG to actively participate in neuroinflammation in the retina. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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21 pages, 4205 KiB

Open AccessArticle

Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation

by Jae-Hong Kim, Md Habibur Rahman, Donghwi Park, Myungjin Jo, Hyung-Jun Kim and Kyoungho Suk

Cells 2021, 10(3), 676; https://doi.org/10.3390/cells10030676 - 18 Mar 2021

Cited by 13 | Viewed by 3563

Abstract

Transactive response DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been implicated in numerous aspects of the mRNA life cycle, as well as in cell toxicity and neuroinflammation. In [...] Read more.

Transactive response DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been implicated in numerous aspects of the mRNA life cycle, as well as in cell toxicity and neuroinflammation. In this study, we used the toxicity of the TDP-43 expression in Saccharomyces cerevisiae as an assay to identify TDP-43 genetic interactions. Specifically, we transformed human TDP-43 cDNAs of wild-type or disease-associated mutants (M337V and Q331K) en masse into 4653 homozygous diploid yeast deletion mutants and then used next-generation sequencing readouts of growth to identify yeast toxicity modifiers. Genetic interaction analysis provided a global view of TDP-43 pathways, some of which are known to be involved in cellular metabolic processes. Selected putative loci with the potential of genetic interactions with TDP-43 were assessed for associations with neurotoxicity and inflammatory activation of astrocytes. The pharmacological inhibition of succinate dehydrogenase flavoprotein subunit A (SDHA) and voltage-dependent anion-selective channel 3 (VDAC3) suppressed TDP-43-induced expression of proinflammatory cytokines in astrocytes, indicating the critical roles played by SDHA and VDAC3 in TDP-43 pathways during inflammatory activation of astrocytes and neuroinflammation. Thus, the findings of our TDP-43 genetic interaction screen provide a global landscape of TDP-43 pathways and may help improve our understanding of the roles of glia and neuroinflammation in ALS and FTD pathogenesis. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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13 pages, 1962 KiB

Open AccessArticle

New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain

by Tomohiro Yamashita, Sawako Kamikaseda, Aya Tanaka, Hidetoshi Tozaki-Saitoh, Jose M. M. Caaveiro, Kazuhide Inoue and Makoto Tsuda

Cells 2021, 10(2), 434; https://doi.org/10.3390/cells10020434 - 18 Feb 2021

Cited by 14 | Viewed by 3915

Abstract

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states [...] Read more.

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca²⁺ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca²⁺ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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Review

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14 pages, 2310 KiB

Open AccessReview

Role of Aldynoglia Cells in Neuroinflammatory and Neuroimmune Responses after Spinal Cord Injury

by Vinnitsa Buzoianu-Anguiano, Mabel Torres-Llacsa and Ernesto Doncel-Pérez

Cells 2021, 10(10), 2783; https://doi.org/10.3390/cells10102783 - 17 Oct 2021

Cited by 19 | Viewed by 3787

Abstract

Aldynoglia are growth-promoting cells with a morphology similar to radial glia and share properties and markers with astrocytes and Schwann cells. They are distributed in several locations throughout the adult central nervous system, where the cells of the aldynoglia interact and respond to [...] Read more.

Aldynoglia are growth-promoting cells with a morphology similar to radial glia and share properties and markers with astrocytes and Schwann cells. They are distributed in several locations throughout the adult central nervous system, where the cells of the aldynoglia interact and respond to the signals of the immune cells. After spinal cord injury (SCI), the functions of resident aldynoglia, identified as ependymocytes, tanycytes, and ependymal stem cells (EpSCs) of the spinal cord are crucial for the regeneration of spinal neural tissue. These glial cells facilitate axonal regrowth and remyelination of injured axons. Here, we review the influence of M1 or M2 macrophage/microglia subpopulations on the fate of EpSCs during neuroinflammation and immune responses in the acute, subacute, and chronic phases after SCI. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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24 pages, 6333 KiB

Open AccessReview

Astrocytic Regulation of Neural Circuits Underlying Behaviors

by Sun-Nyoung Hwang, Jae Seung Lee, Kain Seo and Hyosang Lee

Cells 2021, 10(2), 296; https://doi.org/10.3390/cells10020296 - 1 Feb 2021

Cited by 15 | Viewed by 5495

Abstract

Astrocytes, characterized by a satellite-like morphology, are the most abundant type of glia in the central nervous system. Their main functions have been thought to be limited to providing homeostatic support for neurons, but recent studies have revealed that astrocytes actually actively interact [...] Read more.

Astrocytes, characterized by a satellite-like morphology, are the most abundant type of glia in the central nervous system. Their main functions have been thought to be limited to providing homeostatic support for neurons, but recent studies have revealed that astrocytes actually actively interact with local neural circuits and play a crucial role in information processing and generating physiological and behavioral responses. Here, we review the emerging roles of astrocytes in many brain regions, particularly by focusing on intracellular changes in astrocytes and their interactions with neurons at the molecular and neural circuit levels. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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25 pages, 2500 KiB

Open AccessReview

Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

by Mehdi Ghasemi, Kiandokht Keyhanian and Catherine Douthwright

Cells 2021, 10(2), 249; https://doi.org/10.3390/cells10020249 - 28 Jan 2021

Cited by 18 | Viewed by 7281

Abstract

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding [...] Read more.

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD. Full article

(This article belongs to the Special Issue The Function of Glial Cells in the Neuroinflammatory and Neuroimmunological Responses)

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