International Journal of Molecular Sciences

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14 pages, 4063 KiB

Open AccessArticle

Cerebral Pericytes and Endothelial Cells Communicate through Inflammasome-Dependent Signals

by Mihály Kozma, Ádám Mészáros, Ádám Nyúl-Tóth, Kinga Molnár, Laura Costea, Zsófia Hernádi, Csilla Fazakas, Attila E. Farkas, Imola Wilhelm and István A. Krizbai

Int. J. Mol. Sci. 2021, 22(11), 6122; https://doi.org/10.3390/ijms22116122 - 6 Jun 2021

Cited by 9 | Viewed by 3247

Abstract

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, [...] Read more.

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1β over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)

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17 pages, 2971 KiB

Open AccessArticle

Treg-Resistant Cytotoxic CD4⁺ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation

by Cindy Hoeks, Marjan Vanheusden, Liesbet M. Peeters, Piet Stinissen, Bieke Broux and Niels Hellings

Int. J. Mol. Sci. 2021, 22(11), 5660; https://doi.org/10.3390/ijms22115660 - 26 May 2021

Cited by 9 | Viewed by 3982

Abstract

Cytotoxic CD4⁺ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T [...] Read more.

Cytotoxic CD4⁺ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)

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13 pages, 1894 KiB

Open AccessArticle

Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis

by Elien Wouters, Elien Grajchen, Winde Jorissen, Tess Dierckx, Suzan Wetzels, Melanie Loix, Marie Paule Tulleners, Bart Staels, Piet Stinissen, Mansour Haidar, Jeroen F. J. Bogie and Jerome J. A. Hendriks

Int. J. Mol. Sci. 2020, 21(23), 9329; https://doi.org/10.3390/ijms21239329 - 7 Dec 2020

Cited by 18 | Viewed by 3472

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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19 pages, 3242 KiB

Open AccessArticle

Adenosine Triphosphate Accumulated Following Cerebral Ischemia Induces Neutrophil Extracellular Trap Formation

by Seung-Woo Kim, Dashdulam Davaanyam, Song-I Seol, Hye-Kyung Lee, Hahnbie Lee and Ja-Kyeong Lee

Int. J. Mol. Sci. 2020, 21(20), 7668; https://doi.org/10.3390/ijms21207668 - 16 Oct 2020

Cited by 30 | Viewed by 3481

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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15 pages, 1727 KiB

Open AccessArticle

HDAC8 Inhibition Reduces Lesional Iba-1+ Cell Infiltration after Spinal Cord Injury without Effects on Functional Recovery

by Sven Hendrix, Selien Sanchez, Elissia Ventriglia and Stefanie Lemmens

Int. J. Mol. Sci. 2020, 21(12), 4539; https://doi.org/10.3390/ijms21124539 - 25 Jun 2020

Cited by 9 | Viewed by 2443

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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19 pages, 5555 KiB

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

by Yong-Ren Chen, Pei-Lun Lai, Yueh Chien, Po-Hui Lee, Ying-Hsiu Lai, Hsin-I Ma, Chia-Yang Shiau and Kuo-Chuan Wang

Int. J. Mol. Sci. 2020, 21(11), 3807; https://doi.org/10.3390/ijms21113807 - 27 May 2020

Cited by 48 | Viewed by 4164

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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14 pages, 1332 KiB

Open AccessReview

Fatty Acid Synthesis in Glial Cells of the CNS

by Aida V. Garcia Corrales, Mansour Haidar, Jeroen F. J. Bogie and Jerome J. A. Hendriks

Int. J. Mol. Sci. 2021, 22(15), 8159; https://doi.org/10.3390/ijms22158159 - 29 Jul 2021

Cited by 31 | Viewed by 5339

Abstract

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing [...] Read more.

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer’s disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying CNS Inflammation)

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22 pages, 740 KiB

Open AccessReview

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury

by Chiara Mele, Valeria Pingue, Marina Caputo, Marco Zavattaro, Loredana Pagano, Flavia Prodam, Antonio Nardone, Gianluca Aimaretti and Paolo Marzullo

Int. J. Mol. Sci. 2021, 22(5), 2686; https://doi.org/10.3390/ijms22052686 - 7 Mar 2021

Cited by 21 | Viewed by 4760

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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24 pages, 943 KiB

Open AccessReview

Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism

by Alexander Pilozzi, Caitlin Carro and Xudong Huang

Int. J. Mol. Sci. 2021, 22(1), 338; https://doi.org/10.3390/ijms22010338 - 30 Dec 2020

Cited by 78 | Viewed by 34446

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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42 pages, 1340 KiB

Open AccessReview

Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease

by Anna Chiarini, Ubaldo Armato, Peng Hu and Ilaria Dal Prà

Int. J. Mol. Sci. 2020, 21(23), 9036; https://doi.org/10.3390/ijms21239036 - 27 Nov 2020

Cited by 43 | Viewed by 4891

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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24 pages, 776 KiB

Open AccessReview

Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

by Alessandra Roggeri, Melissa Schepers, Assia Tiane, Ben Rombaut, Lieve van Veggel, Niels Hellings, Jos Prickaerts, Anna Pittaluga and Tim Vanmierlo

Int. J. Mol. Sci. 2020, 21(20), 7537; https://doi.org/10.3390/ijms21207537 - 13 Oct 2020

Cited by 23 | Viewed by 5054

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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1 pages, 160 KiB

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

by Yong-Ren Chen, Pei-Lun Lai, Yueh Chien, Po-Hui Lee, Ying-Hsiu Lai, Hsin-I Ma, Chia-Yang Shiau and Kuo-Chuan Wang

Int. J. Mol. Sci. 2021, 22(3), 1154; https://doi.org/10.3390/ijms22031154 - 25 Jan 2021

Cited by 1 | Viewed by 2065

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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