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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: closed (30 June 2020) | Viewed by 43554

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Prof. Dr. Michel Salzet

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Guest Editor

INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Université de Lille, F-59000 Lille, France
Interests: proteomics; neuroimmunology; oncoimmunology; dot blot hybridization; immunology; cancer research; elisa; innate immunity; MALDI-TOF MS; amino acids; proteins; enzymes; analytical chemistry

Prof. Dr. Serge Nataf

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Co-Guest Editor

1. Bank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, F-69003 Lyon, France
2. Stem-Cell and Brain Research Institute, 18 Avenue de Doyen Lépine, F-69500 Bron, France
3. Lyon-Est School of Medicine, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69100 Villeurbanne, France
Interests: multiple sclerosis pathophysiology; CNS-targeted autoimmunity; neuroinflammation; computational data mining; systems biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroimmunology represents the field that integrates cross-talk between the immune and nervous systems, but also expression of immune factors in the brain as well as neuroendocrine factors in the immune system. Interactions between the two systems during neurodevelopment, brain homeostasis and brain pathologies are the main interests for neuroimmunologists. The understanding of the role of immune cell infiltration as well as immune factor expression by neural and neuronal cells constitutes the basis of research into brain diseases in terms of their etiology, spreading, cognitive consequences and the possibility of pharmaceutical treatment. Among the major cells implicated in the neuroimmune response, microglia and astrocytes constitute the pillar of the physiological functioning of the nervous system. These cells acts as the link and the sensors of the cognitive or brain pathogenic stresses. Environmental stressors are the major inducers of neuroinflammation that lead to brain disorders. Taken together, this Special Issue is dedicated to the recent research progress in neuroimmunology. The goal is to provide an in-depth understanding of the underlying central impact of the neuroimmune response in brain diseases, and to exploit such knowledge for future therapies, taking into account the immune part of the brain response.

Prof. Dr. Michel Salzet
Prof. Dr. Serge Nataf
Guest Editors

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Published Papers (9 papers)

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Research

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13 pages, 2486 KiB

Open AccessArticle

A Novel Highly Sensitive Method for Measuring Inflammatory Neural-Derived APC Activity in Glial Cell Lines, Mouse Brain and Human CSF

by Valery Golderman, Shany G. Gofrit, Nicola Maggio, Orna Gera, Alexandra Gerasimov, Dar Laks, Joab Chapman and Efrat Shavit-Stein

Int. J. Mol. Sci. 2020, 21(7), 2422; https://doi.org/10.3390/ijms21072422 - 31 Mar 2020

Cited by 3 | Viewed by 2479

Abstract

Background: Neural inflammation is linked to coagulation. Low levels of thrombin have a neuroprotective effect, mediated by activated protein C (APC). We describe a sensitive novel method for the measurement of APC activity at the low concentrations found in neural tissue. Methods: APC activity was measured using a fluorogenic substrate, Pyr-Pro-Arg-AMC, cleaved preferentially by APC. Selectivity was assessed using specific inhibitors and activators. APC levels were measured in human plasma, in glia cell lines, in mice brain slices following mild traumatic brain injury (mTBI) and systemic lipopolysaccharide (LPS) injection, and in cerebrospinal fluid (CSF) taken from viral meningoencephalitis patients and controls. Results: Selectivity required apixaban and alpha-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (NAPAP). APC levels were easily measurable in plasma and were significantly increased by Protac and CaCl₂. APC activity was significantly higher in the microglial compared to astrocytic cell line and specifically lowered by LPS. Brain APC levels were higher in posterior regions and increased by mTBI and LPS. Highly elevated APC activity was measured in viral meningoencephalitis patients CSF. Conclusions: This method is selective and sensitive for the measurement of APC activity that significantly changes during inflammation in cell lines, animal models and human CSF. Full article

(This article belongs to the Special Issue Neuroimmunology)

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12 pages, 2716 KiB

Open AccessArticle

Leucine-Rich Repeat Kinase 2 Controls Inflammatory Cytokines Production through NF-κB Phosphorylation and Antigen Presentation in Bone Marrow-Derived Dendritic Cells

by Makoto Kubo, Ryuichi Nagashima, Mitsue Kurihara, Fumitaka Kawakami, Tatsunori Maekawa, Koji Eshima, Etsuro Ohta, Hirotomo Kato and Fumiya Obata

Int. J. Mol. Sci. 2020, 21(5), 1890; https://doi.org/10.3390/ijms21051890 - 10 Mar 2020

Cited by 7 | Viewed by 3435

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the causal molecule of familial Parkinson’s disease. Although the characteristics of LRRK2 have gradually been revealed, its true physiological functions remain unknown. LRRK2 is highly expressed in immune cells such as B2 cells and macrophages, suggesting that it plays important roles in the immune system. In the present study, we investigate the roles of LRRK2 in the immune functions of dendritic cells (DCs). Bone marrow-derived DCs from both C57BL/6 wild-type (WT) and LRRK2 knockout (KO) mice were induced by culture with granulocyte/macrophage-colony stimulating factor (GM/CSF) in vitro. We observed the differentiation of DCs, the phosphorylation of the transcriptional factors NF-κB, Erk1/2, and p-38 after lipopolysaccharide (LPS) stimulation and antigen-presenting ability by flow cytometry. We also analyzed the production of inflammatory cytokines by ELISA. During the observation period, there was no difference in DC differentiation between WT and LRRK2-KO mice. After LPS stimulation, phosphorylation of NF-κB was significantly increased in DCs from the KO mice. Large amounts of inflammatory cytokines were produced by DCs from KO mice after both stimulation with LPS and infection with Leishmania. CD4⁺ T-cells isolated from antigen-immunized mice proliferated to a significantly greater degree upon coculture with antigen-stimulated DCs from KO mice than upon coculture with DCs from WT mice. These results suggest that LRRK2 may play important roles in signal transduction and antigen presentation by DCs. Full article

(This article belongs to the Special Issue Neuroimmunology)

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15 pages, 2998 KiB

Open AccessArticle

Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration

by Yun Gao, Dezhen Tu, Ru Yang, Chun-Hsien Chu, Jau-Shyong Hong and Hui-Ming Gao

Int. J. Mol. Sci. 2020, 21(2), 465; https://doi.org/10.3390/ijms21020465 - 11 Jan 2020

Cited by 18 | Viewed by 3482

Abstract

Chronic neuroinflammation contributes to the pathogenesis of Parkinson’s disease (PD). However, cellular and molecular mechanisms by which chronic neuroinflammation is formed and maintained remain elusive. This study aimed to explore detailed mechanisms by which anti-inflammatory cytokine interleukin-10 (IL-10) prevented chronic neuroinflammation and neurodegeneration. At 24 h after an intranigral injection of lipopolysaccharide (LPS), levels of NLRP3, pro-caspase-1, pro-IL-1β, active caspase-1, and mature IL-1β in the midbrain were much higher in IL-10^−/− mice than wildtype mice. Mechanistically, IL-10^−/− microglia produced more intracellular reactive oxygen species (iROS) and showed more profound activation of NADPH oxidase (NOX2) than wildtype microglia. Meanwhile, suppression of NOX2-derived iROS production blocked LPS-elicited caspase-1 activation and IL-1β maturation in IL-10^−/− microglia in vitro and in vivo. One month after intranigral LPS injection, IL-10^−/− mice revealed more profound microglial activation and dopaminergic neurodegeneration in the substantia nigra than wildtype mice. Importantly, such PD-like pathological changes were prevented by IL-1β neutralization. Collectively, IL-10 inhibited LPS-elicited production of NOX2-derived iROS thereby suppressing synthesis of NLRP3, pro-caspase-1 and pro-IL-1β and their activation and cleavage. By this mechanism, IL-10 prevented chronic neuroinflammation and neurodegeneration. This study suggested boosting anti-inflammatory effects of IL-10 and suppressing NLRP3 inflammasome activation could be beneficial for PD treatment. Full article

(This article belongs to the Special Issue Neuroimmunology)

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15 pages, 3173 KiB

Open AccessArticle

Dental Pulp Stem Cell-Derived Factors Alleviate Subarachnoid Hemorrhage-Induced Neuroinflammation and Ischemic Neurological Deficits

by Te-Fu Chen, Kuo-We Chen, Yueh Chien, Ying-Hsiu Lai, Sung-Tsang Hsieh, Hsin-Yi Ma, Kou-Chung Wang and Chia-Yang Shiau

Int. J. Mol. Sci. 2019, 20(15), 3747; https://doi.org/10.3390/ijms20153747 - 31 Jul 2019

Cited by 20 | Viewed by 3697

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms. Full article

(This article belongs to the Special Issue Neuroimmunology)

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20 pages, 6308 KiB

Open AccessArticle

Medicinal Leech CNS as a Model for Exosome Studies in the Crosstalk between Microglia and Neurons

by Antonella Raffo-Romero, Tanina Arab, Issa S. Al-Amri, Francoise Le Marrec-Croq, Christelle Van Camp, Quentin Lemaire, Michel Salzet, Jacopo Vizioli, Pierre-Eric Sautiere and Christophe Lefebvre

Int. J. Mol. Sci. 2018, 19(12), 4124; https://doi.org/10.3390/ijms19124124 - 19 Dec 2018

Cited by 27 | Viewed by 5999

Abstract

In healthy or pathological brains, the neuroinflammatory state is supported by a strong communication involving microglia and neurons. Recent studies indicate that extracellular vesicles (EVs), including exosomes and microvesicles, play a key role in the physiological interactions between cells allowing central nervous system (CNS) development and/or integrity. The present report used medicinal leech CNS to investigate microglia/neuron crosstalk from ex vivo approaches as well as primary cultures. The results demonstrated a large production of exosomes from microglia. Their incubation to primary neuronal cultures showed a strong interaction with neurites. In addition, neurite outgrowth assays demonstrated microglia exosomes to exhibit significant neurotrophic activities using at least a Transforming Growth Factor beta (TGF-β) family member, called nGDF (nervous Growth/Differentiation Factor). Of interest, the results also showed an EV-mediated dialog between leech microglia and rat cells highlighting this communication to be more a matter of molecules than of species. Taken together, the present report brings a new insight into the microglia/neuron crosstalk in CNS and would help deciphering the molecular evolution of such a cell communication in brain. Full article

(This article belongs to the Special Issue Neuroimmunology)

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15 pages, 3264 KiB

Open AccessArticle

Effects of Oxytocin on Fear Memory and Neuroinflammation in a Rodent Model of Posttraumatic Stress Disorder

by Sheng-Chiang Wang, Chen-Cheng Lin, Chun-Chuan Chen, Nian-Sheng Tzeng and Yia-Ping Liu

Int. J. Mol. Sci. 2018, 19(12), 3848; https://doi.org/10.3390/ijms19123848 - 03 Dec 2018

Cited by 48 | Viewed by 5839

Abstract

Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterized by fear extinction abnormalities, which involve biological dysfunctions among fear circuit areas in the brain. Oxytocin (OXT) is a neuropeptide that regulates sexual reproduction and social interaction and has recently earned specific attention due to its role in adjusting neurobiological and behavioral correlates of PTSD; however, the mechanism by which this is achieved remains unclear. The present study aimed to examine whether the effects of OXT on traumatic stress-induced abnormalities of fear extinction (specifically induced by single prolonged stress (SPS), an animal model of PTSD) are associated with pro-inflammatory cytokines. Seven days after SPS, rats received intranasal OXT 40 min before a cue-dependent Pavlovian fear conditioning-extinction test in which rats’ freezing degree was used to reflect the outcome of fear extinction. We also measured mRNA expression of IL-1β, IFN-γ, and TNF-α in the medial prefrontal cortex (mPFC), hippocampus, and amygdala at the end of the study, together with plasma oxytocin, corticosterone, IL-1β, IFN-γ, and TNF-α, to reflect the central and peripheral changes of stress-related hormones and cytokines after SPS. Our results suggested that intranasal OXT effectively amends the SPS-impaired behavior of fear extinction retrieval. Moreover, it neurochemically reverses the SPS increase in pro-inflammatory cytokines; thus, IL-1β and IFN-γ can be further blocked by the OXT antagonist atosiban (ASB) in the hippocampus. Peripheral profiles revealed a similar response pattern to SPS of OXT and corticosterone (CORT), and the SPS-induced increase in plasma levels of IL-1β and TNF-α could be reduced by OXT. The present study suggests potential therapeutic effects of OXT in both behavioral and neuroinflammatory profiles of PTSD. Full article

(This article belongs to the Special Issue Neuroimmunology)

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Review

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21 pages, 1116 KiB

Open AccessReview

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives

by Jakub Litak, Cezary Grochowski, Joanna Litak, Ida Osuchowska, Krzysztof Gosik, Elżbieta Radzikowska, Piotr Kamieniak and Jacek Rolinski

Int. J. Mol. Sci. 2020, 21(9), 3114; https://doi.org/10.3390/ijms21093114 - 28 Apr 2020

Cited by 29 | Viewed by 4815

Abstract

Toll-like-receptor (TLR) family members were detected in the central nervous system (CNS). TLR occurrence was noticed and widely described in glioblastomamultiforme (GBM) cells. After ligand attachment, TLR-4 reorients domains and dimerizes, activates an intracellular cascade, and promotes further cytoplasmatic signaling. There is evidence pointing at a strong relation between TLR-4 signaling and micro ribonucleic acid (miRNA) expression. The TLR-4/miRNA interplay changes typical signaling and encourages them to be a target for modern immunotherapy. TLR-4 agonists initiate signaling and promote programmed death ligand-1 (PD-1L) expression. Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression. Another potential target for immunotreatment is connected with limited TLR-4 signaling that promotes Wnt/DKK-3/claudine-5 signaling, resulting in a limitation of GBM invasiveness. Interestingly, TLR-4 expression results in bordering proliferative trends in cancer stem cells (CSC) and GBM. All of these potential targets could bring new hope for patients suffering from this incurable disease. Clinical trials concerning TLR-4 signaling inhibition/promotion in many cancers are recruiting patients. There is still a lot to do in the field of GBM immunotherapy. Full article

(This article belongs to the Special Issue Neuroimmunology)

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17 pages, 1272 KiB

Open AccessReview

Micro RNA Molecules as Modulators of Treatment Resistance, Immune Checkpoints Controllers and Sensitive Biomarkers in Glioblastoma Multiforme

by Marek Mazurek, Jakub Litak, Piotr Kamieniak, Ida Osuchowska, Ryszard Maciejewski, Jacek Roliński, Wiesława Grajkowska and Cezary Grochowski

Int. J. Mol. Sci. 2020, 21(4), 1507; https://doi.org/10.3390/ijms21041507 - 22 Feb 2020

Cited by 17 | Viewed by 4079

Abstract

Based on genome sequencing, it is estimated that over 90% of genes stored in human genetic material are transcribed, but only 3% of them contain the information needed for the production of body proteins. This group also includes micro RNAs representing about 1%–3% of the human genome. Recent studies confirmed the hypothesis that targeting molecules called Immune Checkpoint (IC) open new opportunities to take control over glioblastoma multiforme (GBM). Detection of markers that indicate the presence of the cancer occupies a very important place in modern oncology. This function can be performed by both the cancer cells themselves as well as their components and other substances detected in the patients’ bodies. Efforts have been made for many years to find a suitable marker useful in the diagnosis and monitoring of gliomas, including glioblastoma. Full article

(This article belongs to the Special Issue Neuroimmunology)

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16 pages, 2388 KiB

Open AccessReview

PD-L1/PD-1 Axis in Glioblastoma Multiforme

by Jakub Litak, Marek Mazurek, Cezary Grochowski, Piotr Kamieniak and Jacek Roliński

Int. J. Mol. Sci. 2019, 20(21), 5347; https://doi.org/10.3390/ijms20215347 - 28 Oct 2019

Cited by 118 | Viewed by 9026

Abstract

Glioblastoma (GBM) is the most popular primary central nervous system cancer and has an extremely expansive course. Aggressive tumor growth correlates with short median overall survival (OS) oscillating between 14 and 17 months. The survival rate of patients in a three-year follow up oscillates around 10%. The interaction of the proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) creates an immunoregulatory axis promoting invasion of glioblastoma multiforme cells in the brain tissue. The PD-1 pathway maintains immunological homeostasis and protects against autoimmunity. PD-L1 expression on glioblastoma surface promotes PD-1 receptor activation in microglia, resulting in the negative regulation of T cell responses. Glioblastoma multiforme cells induce PD-L1 secretion by activation of various receptors such as toll like receptor (TLR), epidermal growth factor receptor (EGFR), interferon alpha receptor (IFNAR), interferon-gamma receptor (IFNGR). Binding of the PD-1 ligand to the PD-1 receptor activates the protein tyrosine phosphatase SHP-2, which dephosphorylates Zap 70, and this inhibits T cell proliferation and downregulates lymphocyte cytotoxic activity. Relevant studies demonstrated that the expression of PD-L1 in glioma correlates with WHO grading and could be considered as a tumor biomarker. Studies in preclinical GBM mouse models confirmed the safety and efficiency of monoclonal antibodies targeting the PD-1/PD-L1 axis. Satisfactory results such as significant regression of tumor mass and longer animal survival time were observed. Monoclonal antibodies inhibiting PD-1 and PD-L1 are being tested in clinical trials concerning patients with recurrent glioblastoma multiforme. Full article

(This article belongs to the Special Issue Neuroimmunology)

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