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Neuroinflammation in Neurodegenerative and Neurological Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 71186

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Special Issue Editor

Dr. Vicente Felipo

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Guest Editor

Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
Interests: neuroinflammation; neurotransmission; hepatic encephalopathy; hyperammonemia; cognitive impairment; motor alterations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic neuroinflammation plays a main role in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases and multiple sclerosis, and in other neurological diseases such as schizophrenia, stroke, and hepatic encephalopathy. Neuroinflammation also arises in many pathologies associated with chronic inflammation (such as diabetes and rheumatoid arthritis), which are not traditionally considered as neurological diseases but may also lead to impairment of cognitive and motor function, depression, and other alterations of cerebral function that are mediated by neuroinflammation.

This pathological neuroinflammation is mainly mediated by microglia and astrocytes, which play important immunomodulatory functions in the brain. Neuroinflammation alters the communication between cells in the CNS and leads to altered neurotransmission, which alters cognitive and motor functions and may also led to depression and other deleterious consequences.

Alterations in the peripheral immune system play a key role in the induction of neuroinflammation. There are different mechanisms by which these peripheral changes may be transmitted to the brain, which may or may not involve infiltration into the brain of cells of the peripheral immune system.

This Special Issue welcomes original papers and reviews on any relevant aspect of the mechanisms involved in the induction of neuroinflammation in neurodegenerative and other neurological diseases: the role of microbiota and the gut–brain axis; how peripheral inflammation is transmitted to the brain; the role of cells of the immune system, of endothelial cells and of microglia, of astrocytes and other brain cells, and of the mediators in the communication between these cells (cytokines, chemokines, their receptors, extracellular vesicles including exosomes, etc.); and the molecular mechanisms of the activation of microglia and astrocytes.

Studies on how neuroinflammation alters neurotransmission and leads to cognitive and motor impairment, depression, or other deleterious consequences are also welcome.

New therapeutic approaches to restore these neurological alterations by acting on any target of any step of the processes by which peripheral inflammation leads to neuroinflammation are welcome; how neuroinflammation alters neurotransmission or induces neurodegeneration and how this induces depression or impairment of cognitive and motor function will be also considered.

Dr. Vicente Felipo
Guest Editor

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Keywords

neuroinflammation;
immune system-CNS cross talk;
neurological impairment;
glial activation;
mediators of inflammation: chemokines, interleukins, and extracellular vesicles.

Published Papers (11 papers)

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Research

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15 pages, 2359 KiB

Open AccessArticle

IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

by Anna Escrig, Amalia Molinero, Brenda Méndez, Mercedes Giralt, Gemma Comes, Paula Sanchis, Olaya Fernández-Gayol, Lydia Giménez-Llort, Christoph Becker-Pauly, Stefan Rose-John and Juan Hidalgo

Cells 2020, 9(7), 1605; https://doi.org/10.3390/cells9071605 - 2 Jul 2020

Cited by 10 | Viewed by 3065

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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19 pages, 4026 KiB

Open AccessArticle

CDDO-Me Inhibits Microglial Activation and Monocyte Infiltration by Abrogating NFκB- and p38 MAPK-Mediated Signaling Pathways Following Status Epilepticus

by Ji-Eun Kim, Hana Park, Ji-Eun Lee and Tae-Cheon Kang

Cells 2020, 9(5), 1123; https://doi.org/10.3390/cells9051123 - 1 May 2020

Cited by 15 | Viewed by 2957

Abstract

Following status epilepticus (SE, a prolonged seizure activity), microglial activation, and monocyte infiltration result in the inflammatory responses in the brain that is involved in the epileptogenesis. Therefore, the regulation of microglia/monocyte-mediated neuroinflammation is one of the therapeutic strategies for avoidance of secondary brain injury induced by SE. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), which regulates intracellular redox homeostasis. In addition, CDDO-Me has anti-inflammatory properties that suppress microglial proliferation and its activation, although the underlying mechanisms have not been clarified. In the present study, CDDO-Me ameliorated monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC) following SE, accompanied by abrogating monocyte chemotactic protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α) expressions and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Furthermore, CDDO-Me inhibited nuclear factor-κB (NFκB)-S276 phosphorylation and microglial transformation, independent of Nrf2 expression. Similar to CDDO-Me, SN50 (an NFκB inhibitor) mitigated monocyte infiltration by reducing MCP-1 and p38 MAPK phosphorylation in the FPC following SE. Therefore, these findings suggest, for the first time, that CDDO-Me may attenuate microglia/monocyte-mediated neuroinflammation via modulating NFκB- and p38 MAPK-MCP-1 signaling pathways following SE. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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17 pages, 1630 KiB

Open AccessArticle

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

by Rodrigo B. Mansur, Francheska Delgado-Peraza, Mehala Subramaniapillai, Yena Lee, Michelle Iacobucci, Nelson Rodrigues, Joshua D. Rosenblat, Elisa Brietzke, Victoria E. Cosgrove, Nicole E. Kramer, Trisha Suppes, Charles L. Raison, Sahil Chawla, Carlos Nogueras-Ortiz, Roger S. McIntyre and Dimitrios Kapogiannis

Cells 2020, 9(4), 895; https://doi.org/10.3390/cells9040895 - 6 Apr 2020

Cited by 33 | Viewed by 5273

Abstract

Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab’s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab’s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ² = 9.275, p = 0.026), NF-κB (χ² = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα)α (χ² = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ² = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = −0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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18 pages, 2112 KiB

Open AccessArticle

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

by Chien-Tai Hong, Kai-Yun Chen, Weu Wang, Jing-Yuan Chiu, Dean Wu, Tsu-Yi Chao, Chaur-Jong Hu, Kai-Yin David Chau and Oluwaseun Adebayo Bamodu

Cells 2020, 9(3), 740; https://doi.org/10.3390/cells9030740 - 17 Mar 2020

Cited by 60 | Viewed by 5798

Abstract

Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson’s disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Methods: Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. Conclusions: These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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16 pages, 3410 KiB

Open AccessArticle

Extracellular Vesicles from Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats

by Paula Izquierdo-Altarejos, Andrea Cabrera-Pastor, Hernan Gonzalez-King, Carmina Montoliu and Vicente Felipo

Cells 2020, 9(3), 572; https://doi.org/10.3390/cells9030572 - 28 Feb 2020

Cited by 19 | Viewed by 2933

Abstract

Minimal hepatic encephalopathy is associated with changes in the peripheral immune system which are transferred to the brain, leading to neuroinflammation and thus to cognitive and motor impairment. Mechanisms by which changes in the immune system induce cerebral alterations remain unclear. Extracellular vesicles (EVs) seem to play a role in this process in certain pathologies. The aim of this work was to assess whether EVs play a role in the induction of neuroinflammation in cerebellum and motor incoordination by chronic hyperammonemia. We characterized the differences in protein cargo of EVs from plasma of hyperammonemic and control rats by proteomics and Western blot. We assessed whether injection of EVs from hyperammonemic to normal rats induces changes in neuroinflammation in cerebellum and motor incoordination similar to those exhibited by hyperammonemic rats. We found that hyperammonemia increases EVs amount and alters their protein cargo. Differentially expressed proteins are mainly associated with immune system processes. Injected EVs enter Purkinje neurons and microglia. Injection of EVs from hyperammonemic, but not from control rats, induces motor incoordination, which is mediated by neuroinflammation, microglia and astrocytes activation and increased IL-1β, TNFα, its receptor TNFR1, NF-κB in microglia, glutaminase I, and GAT3 in cerebellum. Plasma EVs from hyperammonemic rats carry molecules necessary and sufficient to trigger neuroinflammation in cerebellum and the mechanisms leading to motor incoordination. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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18 pages, 4532 KiB

Open AccessArticle

Interleukin-6 Derived from the Central Nervous System May Influence the Pathogenesis of Experimental Autoimmune Encephalomyelitis in a Cell-Dependent Manner

by Paula Sanchis, Olaya Fernández-Gayol, Gemma Comes, Anna Escrig, Mercedes Giralt, Richard D. Palmiter and Juan Hidalgo

Cells 2020, 9(2), 330; https://doi.org/10.3390/cells9020330 - 31 Jan 2020

Cited by 18 | Viewed by 4542

Abstract

Background: Interleukin-6 (IL-6) is a pleiotropic and multifunctional cytokine that plays a critical role in induction of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Although EAE has always been considered a peripherally elicited disease, Il6 expression exclusively within central nervous system is sufficient to induce EAE development. Neurons, astrocytes, and microglia can secrete and respond to IL-6. Methods: To dissect the relevance of each cell source for establishing EAE, we generated and immunized conditional Il6 knockout mice for each of these cell types with myelin oligodendrocyte glycoprotein 35-55 (MOG_35-55) peptide dissolved in complete Freund’s adjuvant (CFA) and supplemented with Mycobacterium tuberculosis. Results and conclusions: The combined results reveal a minor role for Il6 expression in both astrocytes and microglia for symptomatology and neuropathology of EAE, whereas neuronal Il6 expression was not relevant for the variables analyzed. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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16 pages, 2735 KiB

Open AccessFeature PaperArticle

Characterization of Mesenchymal Stem Cells Derived from Patients with Cerebellar Ataxia: Downregulation of the Anti-Inflammatory Secretome Profile

by Jong-Heon Kim, Jin Han, Donggun Seo, Jong Hyuk Yoon, Dongyeong Yoon, Jungwan Hong, Sang Ryong Kim, Min Sung Kim, Tae Yong Lee, Kyung Suk Kim, Pan-Woo Ko, Ho-Won Lee and Kyoungho Suk

Cells 2020, 9(1), 212; https://doi.org/10.3390/cells9010212 - 15 Jan 2020

Cited by 9 | Viewed by 3668

Abstract

Mesenchymal stem cell (MSC) therapy is a promising alternative approach for the treatment of neurodegenerative diseases, according to its neuroprotective and immunomodulatory potential. Despite numerous clinical trials involving autologous MSCs, their outcomes have often been unsuccessful. Several reports have indicated that MSCs from patients have low capacities in terms of the secretion of neurotrophic or anti-inflammatory factors, which might be associated with cell senescence or disease severity. Therefore, a new strategy to improve their capacities is required for optimal efficacy of autologous MSC therapy. In this study, we compared the secretory potential of MSCs among cerebellar ataxia patients (CA-MSCs) and healthy individuals (H-MSCs). Our results, including secretome analysis findings, revealed that CA-MSCs have lower capacities in terms of proliferation, oxidative stress response, motility, and immunomodulatory functions when compared with H-MSCs. The functional differences were validated in a scratch wound healing assay and neuron-glia co-cultures. In addition, the neuroprotective and immunoregulatory protein follistatin-like 1 (FSTL1) was identified as one of the downregulated proteins in the CA-MSC secretome, with suppressive effects on proinflammatory microglial activation. Our study findings suggest that targeting aspects of the downregulated anti-inflammatory secretome, such as FSTL1, might improve the efficacy of autologous MSC therapy for CA. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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Review

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46 pages, 2616 KiB

Open AccessReview

Microglia: Agents of the CNS Pro-Inflammatory Response

by José A. Rodríguez-Gómez, Edel Kavanagh, Pinelopi Engskog-Vlachos, Mikael K.R. Engskog, Antonio J. Herrera, Ana M. Espinosa-Oliva, Bertrand Joseph, Nabil Hajji, José L. Venero and Miguel A. Burguillos

Cells 2020, 9(7), 1717; https://doi.org/10.3390/cells9071717 - 17 Jul 2020

Cited by 168 | Viewed by 12531

Abstract

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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33 pages, 2763 KiB

Open AccessFeature PaperReview

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

by Marta Pajares, Ana I. Rojo, Gina Manda, Lisardo Boscá and Antonio Cuadrado

Cells 2020, 9(7), 1687; https://doi.org/10.3390/cells9071687 - 14 Jul 2020

Cited by 336 | Viewed by 19945

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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22 pages, 1305 KiB

Open AccessReview

Dementia, Depression, and Associated Brain Inflammatory Mechanisms after Spinal Cord Injury

by Yun Li, Tuoxin Cao, Rodney M. Ritzel, Junyun He, Alan I. Faden and Junfang Wu

Cells 2020, 9(6), 1420; https://doi.org/10.3390/cells9061420 - 8 Jun 2020

Cited by 39 | Viewed by 5181

Abstract

Evaluation of the chronic effects of spinal cord injury (SCI) has long focused on sensorimotor deficits, neuropathic pain, bladder/bowel dysfunction, loss of sexual function, and emotional distress. Although not well appreciated clinically, SCI can cause cognitive impairment including deficits in learning and memory, executive function, attention, and processing speed; it also commonly leads to depression. Recent large-scale longitudinal population-based studies indicate that patients with isolated SCI (without concurrent brain injury) are at a high risk of dementia associated with substantial cognitive impairments. Yet, little basic research has addressed potential mechanisms for cognitive impairment and depression after injury. In addition to contributing to disability in their own right, these changes can adversely affect rehabilitation and recovery and reduce quality of life. Here, we review clinical and experimental work on the complex and varied responses in the brain following SCI. We also discuss potential mechanisms responsible for these less well-examined, important SCI consequences. In addition, we outline the existing and developing therapeutic options aimed at reducing SCI-induced brain neuroinflammation and post-injury cognitive and emotional impairments. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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15 pages, 875 KiB

Open AccessReview

Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease

by Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin and Jean-Noël Vallée

Cells 2020, 9(2), 314; https://doi.org/10.3390/cells9020314 - 28 Jan 2020

Cited by 31 | Viewed by 4357

Abstract

Parkinson’s disease (PD) is one of the main neurodegenerative disease characterized by a progressive degeneration of neurons constituted by dopamine in the substantia nigra pars compacta. The etiologies of PD remain unclear. Aging is the main risk factor for PD. Aging could dysregulate molecular pathways controlling cell homeostatic mechanisms. PD cells are the sites of several metabolic abnormalities including neuroinflammation and oxidative stress. Metabolic structures are driven by circadian rhythms. Biologic rhythms are complex systems interacting with the environment and controlling several physiological pathways. Recent findings have shown that the dysregulation of the circadian rhythms is correlated with PD and its metabolic dysregulations. This review is focused on the key role of circadian rhythms and their impact on neuroinflammation and oxidative stress in Parkinson’s disease. Full article

(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)

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