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Special Issue "Molecular Mechanisms Underlying CNS Inflammation"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editors

Prof. Dr. Jerome Hendriks
Website
Guest Editor
Hasselt Univ, Biomed Onderzoeksinst & Transnat Univ Limburg, Sch Life Sci, B-3500 Hasselt, Belgium
Dr. Jeroen Bogie
Website
Guest Editor
BIOMED, School of Life Sciences, Hasselt University, 3590 Diepenbeek, Belgium

Special Issue Information

Dear Colleagues,

The immune system underlies the pathology of many neurological diseases but is also instrumental for the resolution of inflammation and induction of repair. The trigger for activation of the immune system in these diseases may be derived from within the central nervous system (CNS), as seen in, e.g., Alzheimer’s disease or CNS trauma, or systemic immune cell activation may lead to the onset of CNS disease, as is assumed in, e.g., autoimmune diseases such as multiple sclerosis or neuromyelitis optica. Recently, it has become clear that immune mediators also have a key role in resolving inflammatory responses and are crucial for inducing CNS repair. The suppression of detrimental immune responses and the stimulation of beneficial immune responses are considered promising strategies to halt the progression of neurological disease. However, we have just started to comprehend the complex regulation of immune cell function and its interaction with resident brain cells and other body systems such as metabolic pathways, the endocrine system, diet, the microbiome, and the cardiovascular system. Elucidating the molecular mechanisms that regulate the immune system in CNS diseases is key for our understanding of the disease pathology and the development of novel, more effective treatments.

Prof. Dr. Jerome Hendriks
Dr. Jeroen Bogie
Guest Editors

Manuscript Submission Information

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Keywords

  • Neuroinflammation
  • Central nervous system
  • Immune system
  • Neurological disease
  • CNS repair

Published Papers (9 papers)

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Research

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Open AccessArticle
Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis
Int. J. Mol. Sci. 2020, 21(23), 9329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239329 - 07 Dec 2020
Viewed by 490
Abstract
Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it [...] Read more.
Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to determine to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-associated proinflammatory cytokines mimicked this reduction in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced reduction in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessArticle
Adenosine Triphosphate Accumulated Following Cerebral Ischemia Induces Neutrophil Extracellular Trap Formation
Int. J. Mol. Sci. 2020, 21(20), 7668; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207668 - 16 Oct 2020
Viewed by 406
Abstract
In ischemic stroke, neutrophils infiltrate damaged brain tissue immediately following the ischemic insult and aggravate inflammation via various mechanisms which include neutrophil extracellular traps (NETs) formation. In the present study, we showed that adenosine triphosphate (ATP), a DAMP molecule, accumulates in the brain [...] Read more.
In ischemic stroke, neutrophils infiltrate damaged brain tissue immediately following the ischemic insult and aggravate inflammation via various mechanisms which include neutrophil extracellular traps (NETs) formation. In the present study, we showed that adenosine triphosphate (ATP), a DAMP molecule, accumulates in the brain and induces NETosis in brain parenchyma and in circulating neutrophils (PMNs) isolated from a murine model of stroke induced by middle cerebral artery occlusion (MCAO). Expression of peptidylarginine deiminase-4 (PAD4), which induces citrullination of histones H3 (CitH3) and initiates NETosis, was significantly enhanced in brain parenchyma and blood PMNs following MCAO. ATP or BzATP (a prototypic P2X7R agonist) significantly enhanced the inductions of PAD4 and CitH3 in a P2X7R-dependent manner and intracellular Ca2+ influx, PKCα activation, and NADPH oxidase-dependent reactive oxygen species (ROS) production play critical roles in this ATP-P2X7R-mediated NETosis. In our MCAO animal model, NETosis was markedly suppressed by treatment with apyrase, an enzyme hydrolyzing ATP, but enhanced by co-treatment of BzATP, confirming ATP-P2X7R-mediated NETosis. Since ATP not only induced NETosis but was also extruded after NETosis, our results indicate that ATP accumulated in the ischemic brain induces NETosis, mediating a cross-talk linking NETosis with neuronal damage that might aggravate inflammation and brain damage. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessArticle
HDAC8 Inhibition Reduces Lesional Iba-1+ Cell Infiltration after Spinal Cord Injury without Effects on Functional Recovery
Int. J. Mol. Sci. 2020, 21(12), 4539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124539 - 25 Jun 2020
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Abstract
Pan-histone deacetylase (HDAC) inhibition with valproic acid (VPA) has beneficial effects after spinal cord injury (SCI), although with side effects. We focused on specific HDAC8 inhibition, because it is known to reduce anti-inflammatory mediators produced by macrophages (Mφ). We hypothesized that HDAC8 inhibition [...] Read more.
Pan-histone deacetylase (HDAC) inhibition with valproic acid (VPA) has beneficial effects after spinal cord injury (SCI), although with side effects. We focused on specific HDAC8 inhibition, because it is known to reduce anti-inflammatory mediators produced by macrophages (Mφ). We hypothesized that HDAC8 inhibition improves functional recovery after SCI by reducing pro-inflammatory classically activated Mφ. Specific HDAC8 inhibition with PCI-34051 reduced the numbers of perilesional Mφ as measured by histological analyses, but did not improve functional recovery (Basso Mouse Scale). We could not reproduce the published improvement of functional recovery described in contusion SCI models using VPA in our T-cut hemisection SCI model. The presence of spared fibers might be the underlying reason for the conflicting data in different SCI models. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessArticle
Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson’s Disease
Int. J. Mol. Sci. 2020, 21(11), 3807; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113807 - 27 May 2020
Cited by 4 | Viewed by 845
Abstract
Parkinson’s disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem [...] Read more.
Parkinson’s disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased α-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor β1 (TGF-β1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Review

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Open AccessReview
Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury
Int. J. Mol. Sci. 2021, 22(5), 2686; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052686 (registering DOI) - 07 Mar 2021
Abstract
The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence [...] Read more.
The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessReview
Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism
Int. J. Mol. Sci. 2021, 22(1), 338; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010338 - 30 Dec 2020
Viewed by 609
Abstract
β-Endorphins are peptides that exert a wide variety of effects throughout the body. Produced through the cleavage pro-opiomelanocortin (POMC), β-endorphins are the primarily agonist of mu opioid receptors, which can be found throughout the body, brain, and cells of the immune system that [...] Read more.
β-Endorphins are peptides that exert a wide variety of effects throughout the body. Produced through the cleavage pro-opiomelanocortin (POMC), β-endorphins are the primarily agonist of mu opioid receptors, which can be found throughout the body, brain, and cells of the immune system that regulate a diverse set of systems. As an agonist of the body’s opioid receptors, β-endorphins are most noted for their potent analgesic effects, but they also have their involvement in reward-centric and homeostasis-restoring behaviors, among other effects. These effects have implicated the peptide in psychiatric and neurodegenerative disorders, making it a research target of interest. This review briefly summarizes the basics of endorphin function, goes over the behaviors and regulatory pathways it governs, and examines the variability of β-endorphin levels observed between normal and disease/disorder affected individuals. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessReview
Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease
Int. J. Mol. Sci. 2020, 21(23), 9036; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239036 - 27 Nov 2020
Viewed by 455
Abstract
Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer’s disease (AD). However, the underlying pathogenetic mechanisms are still much [...] Read more.
Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer’s disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD’s neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD’s three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca2+ and Aβs and promotes the spread of both Ca2+ dyshomeostasis and AD’s three main drivers, causing a progressive neurons’ death. Since CaSR’s negative allosteric modulators block all these effects, CaSR’s candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Open AccessReview
Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation
Int. J. Mol. Sci. 2020, 21(20), 7537; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207537 - 13 Oct 2020
Viewed by 476
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective [...] Read more.
Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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Other

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Open AccessErratum
Erratum: Chen, Y.-R., et al. Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 3807
Int. J. Mol. Sci. 2021, 22(3), 1154; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031154 - 25 Jan 2021
Viewed by 370
Abstract
The authors regret to have made a mistake in publishing this paper [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)
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