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New Advances in Neuroinflammation
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New Advances in Neuroinflammation

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

Deadline for manuscript submissions: 30 September 2024 | Viewed by 11816

Special Issue Editors

Dr. John W. Chen

E-Mail Website
Guest Editor
Institute for Innovation in Imaging and Center for Systems Biology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Interests: microglia, macrophages; immune response; inflammation; neuroinflammation; oxidative stress; molecular imaging; neurological diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Michael Breckwoldt

E-Mail Website
Guest Editor
Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
Interests: neuroimmunology; neuroscience; imaging; biomarkers; molecular imaging; experimental autoimmune encephalomyelitis; macrophage; redox signaling; inflammation

Special Issue Information

Dear Colleagues,

Neuroinflammation is a key immune response observed in many neurological and neurodegenerative diseases. While an appropriate immune response can be beneficial, aberrant activation of this response may recruit excessive inflammatory cells to cause damage. Thus, neuroinflammation can exert damaging as well as beneficial effects depending on the context. Because the central nervous system is separated from the periphery by the blood–brain barrier that creates an immune-privileged site, it has its own unique immune cells and immune response. Moreover, neuroinflammation can compromise the blood–brain barrier, causing an influx of peripheral immune cells and soluble factors. Recent advances have brought a deeper understanding of neuroinflammation through liquid and imaging biomarkers in animal models and patients that can be leveraged to develop more potent (immuno)therapies to improve patient selection, monitoring, stratification, and outcomes.

This Special Issue aims to provide a collection of the current knowledge and advances in neuroinflammation and associated technologies and diseases. Reviews and original research articles in experimental studies are welcome.

Dr. John W. Chen
Dr. Michael Breckwoldt
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuroinflammation
  • biomarkers
  • neurodegeneration
  • microglia
  • astrocytes
  • oligodendrocytes
  • neurological diseases
  • blood-brain barrier
  • imaging

Published Papers (8 papers)

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Research

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16 pages, 5424 KiB  
Article
Taming Microglia in Alzheimer’s Disease: Exploring Potential Implications of Choline Alphoscerate via α7 nAChR Modulation
by Anna Flavia Cantone, Chiara Burgaletto, Giulia Di Benedetto, Anna Pannaccione, Agnese Secondo, Carlo Maria Bellanca, Egle Augello, Antonio Munafò, Paola Tarro, Renato Bernardini and Giuseppina Cantarella
Cells 2024, 13(4), 309; https://doi.org/10.3390/cells13040309 - 07 Feb 2024
Cited by 1 | Viewed by 876
Abstract
Alzheimer’s disease (AD), marked by cognitive impairment, predominantly affects the brain regions regulated by cholinergic innervation, such as the cerebral cortex and hippocampus. Cholinergic dysfunction, a key contributor to age-related cognitive decline, has spurred investigations into potential therapeutic interventions. We have previously shown [...] Read more.
Alzheimer’s disease (AD), marked by cognitive impairment, predominantly affects the brain regions regulated by cholinergic innervation, such as the cerebral cortex and hippocampus. Cholinergic dysfunction, a key contributor to age-related cognitive decline, has spurred investigations into potential therapeutic interventions. We have previously shown that choline alphoscerate (α-GPC), a cholinergic neurotransmission-enhancing agent, protects from Aβ-mediated neurotoxicity. Herein, we investigated the effects of α-GPC on the microglial phenotype in response to Aβ via modulation of the nicotinic alpha-7 acetylcholine receptor (α7 nAChR). BV2 microglial cells were pre-treated for 1 h with α-GPC and were treated for 24, 48, and 72 h with Aβ1–42 and/or α-BTX, a selective α7nAchR antagonist. Fluorescent immunocytochemistry and Western blot analysis showed that α-GPC was able to antagonize Aβ-induced inflammatory effects. Of note, α-GPC exerted its anti-inflammatory effect by directly activating the α7nAChR receptor, as suggested by the induction of an increase in [Ca2+]i and Ach-like currents. Considering that cholinergic transmission appears crucial in regulating the inflammatory profiles of glial cells, its modulation emerges as a potential pharmaco-therapeutic target to improve outcomes in inflammatory neurodegenerative disorders, such as AD. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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17 pages, 4612 KiB  
Article
Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic–Ischaemic Brain Injury in Rats
by Madeleine J. Smith, Tayla Penny, Yen Pham, Amy E. Sutherland, Graham Jenkin, Michael C. Fahey, Madison C. B. Paton, Megan Finch-Edmondson, Suzanne L. Miller and Courtney A. McDonald
Cells 2023, 12(22), 2659; https://doi.org/10.3390/cells12222659 - 20 Nov 2023
Viewed by 880
Abstract
(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant [...] Read more.
(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic–ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (p < 0.05 compared to control). In contrast, only the highest dose of tacrolimus administered post-HI (0.25 mg/kg/day) reduced brain infarct size (p < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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12 pages, 2156 KiB  
Article
Cytokine Profiling in Human iPSC-Derived Dopaminergic Neuronal and Microglial Cultures
by Evelyn Knappe, Franziska Rudolph, Christine Klein and Philip Seibler
Cells 2023, 12(21), 2535; https://doi.org/10.3390/cells12212535 - 27 Oct 2023
Viewed by 1192
Abstract
Aside from the degeneration of dopaminergic neurons, inflammation is a key component in the movement disorder Parkinson’s disease (PD). Microglia activation as well as elevated cytokine levels were observed in the brains of PD patients, but the specific role of microglia in the [...] Read more.
Aside from the degeneration of dopaminergic neurons, inflammation is a key component in the movement disorder Parkinson’s disease (PD). Microglia activation as well as elevated cytokine levels were observed in the brains of PD patients, but the specific role of microglia in the disease process is unknown. Here, we generate human cellular models by differentiating iPSCs into dopaminergic neurons and microglia. We combine these cells in co-culture to perform cytokine profiling, representing the final functional outcome of various signaling pathways. For this, we used unstimulated conditions and treatment with inflammatory stressors. Importantly, only co-cultures but not the monocultures responded to IL-1β treatment suggesting co-culture-related crosstalk. Moreover, we identified the main types of released cytokines and chemokines in this model system and found a preference for the activation of the chemotaxis pathway in response to all treatments, which informs future studies on the cell-type-specific reaction to inflammatory stimulation. Finally, we detected protein level changes in PD risk factor GPNMB upon stress in microglia, further confirming the link between PD-associated genes and inflammation in human-derived cellular models. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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19 pages, 3627 KiB  
Article
Differential Susceptibility of Ex Vivo Primary Glioblastoma Tumors to Oncolytic Effect of Modified Zika Virus
by Gustavo Garcia, Jr., Nikhil Chakravarty, Sophia Paiola, Estrella Urena, Priya Gyani, Christopher Tse, Samuel W. French, Moise Danielpour, Joshua J. Breunig, David A. Nathanson and Vaithilingaraja Arumugaswami
Cells 2023, 12(19), 2384; https://doi.org/10.3390/cells12192384 - 29 Sep 2023
Cited by 1 | Viewed by 1616
Abstract
Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and the invasive nature of these cells decrease the likely efficacy of [...] Read more.
Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and the invasive nature of these cells decrease the likely efficacy of traditional cancer treatments, thus requiring research into novel treatment options. The use of oncolytic viruses as potential therapeutics has been researched for some time. Zika virus (ZIKV) has demonstrated oncotropism and oncolytic effects on GBM stem cells (GSCs). To address the need for safe and effective GBM treatments, we designed an attenuated ZIKV strain (ZOL-1) that does not cause paralytic or neurological diseases in mouse models compared with unmodified ZIKV. Importantly, we found that patient-derived GBM tumors exhibited susceptibility (responders) and non-susceptibility (non-responders) to ZOL-1-mediated tumor cell killing, as evidenced by differential apoptotic cell death and cell viability upon ZOL-1 treatment. The oncolytic effect observed in responder cells was seen both in vitro in neurosphere models and in vivo upon xenograft. Finally, we observed that the use of ZOL-1 as combination therapy with multiple PI3K-AKT inhibitors in non-responder GBM resulted in enhanced chemotherapeutic efficacy. Altogether, this study establishes ZOL-1 as a safe and effective treatment against GBM and provides a foundation to conduct further studies evaluating its potential as an effective adjuvant with other chemotherapies and kinase inhibitors. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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24 pages, 10835 KiB  
Article
Regulation of Microglial Signaling by Lyn and SHIP-1 in the Steady-State Adult Mouse Brain
by Erskine Chu, Richelle Mychasiuk, Evelyn Tsantikos, April L. Raftery, Elan L’Estrange-Stranieri, Larissa K. Dill, Bridgette D. Semple and Margaret L. Hibbs
Cells 2023, 12(19), 2378; https://doi.org/10.3390/cells12192378 - 28 Sep 2023
Viewed by 1015
Abstract
Chronic neuroinflammation and glial activation are associated with the development of many neurodegenerative diseases and neuropsychological disorders. Recent evidence suggests that the protein tyrosine kinase Lyn and the lipid phosphatase SH2 domain-containing inositol 5′ phosphatase-1 (SHIP-1) regulate neuroimmunological responses, but their homeostatic roles [...] Read more.
Chronic neuroinflammation and glial activation are associated with the development of many neurodegenerative diseases and neuropsychological disorders. Recent evidence suggests that the protein tyrosine kinase Lyn and the lipid phosphatase SH2 domain-containing inositol 5′ phosphatase-1 (SHIP-1) regulate neuroimmunological responses, but their homeostatic roles remain unclear. The current study investigated the roles of Lyn and SHIP-1 in microglial responses in the steady-state adult mouse brain. Young adult Lyn−/− and SHIP-1−/− mice underwent a series of neurobehavior tests and postmortem brain analyses. The microglial phenotype and activation state were examined by immunofluorescence and flow cytometry, and neuroimmune responses were assessed using gene expression analysis. Lyn−/− mice had an unaltered behavioral phenotype, neuroimmune response, and microglial phenotype, while SHIP-1−/− mice demonstrated reduced explorative activity and exhibited microglia with elevated activation markers but reduced granularity. In addition, expression of several neuroinflammatory genes was increased in SHIP-1−/− mice. In response to LPS stimulation ex vivo, the microglia from both Lyn−/− and SHIP-1−/− showed evidence of hyper-activity with augmented TNF-α production. Together, these findings demonstrate that both Lyn and SHIP-1 have the propensity to control microglial responses, but only SHIP-1 regulates neuroinflammation and microglial activation in the steady-state adult brain, while Lyn activity appears dispensable for maintaining brain homeostasis. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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21 pages, 6334 KiB  
Article
Emerging Role of Kinin B1 Receptor in Persistent Neuroinflammation and Neuropsychiatric Symptoms in Mice Following Recovery from SARS-CoV-2 Infection
by Srinivas Sriramula, Drew Theobald, Rohan Umesh Parekh, Shaw M. Akula, Dorcas P. O’Rourke and Jeffrey B. Eells
Cells 2023, 12(16), 2107; https://doi.org/10.3390/cells12162107 - 19 Aug 2023
Cited by 3 | Viewed by 1430
Abstract
Evidence suggests that patients with long COVID can experience neuropsychiatric, neurologic, and cognitive symptoms. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent symptoms are unknown. Here we establish an animal model of long-lasting [...] Read more.
Evidence suggests that patients with long COVID can experience neuropsychiatric, neurologic, and cognitive symptoms. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent symptoms are unknown. Here we establish an animal model of long-lasting effects on the brain by eliciting mild disease in K18-hACE2 mice. Male and female K18-hACE2 mice were infected with 4 × 103 TCID50 of SARS-CoV-2 and, following recovery from acute infection, were tested in the open field, zero maze, and Y maze, starting 30 days post infection. Following recovery from SARS-CoV-2 infection, K18-hACE2 mice showed the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also had elevated expression of B1R and inflammatory markers in the brain and exhibited behavioral alterations such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential for using this model of high sensitivity to SARS-CoV-2 to investigate mechanisms contributing to long COVID symptoms in at-risk populations. These results further suggest that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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Review

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28 pages, 2796 KiB  
Review
Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders
by Jessica Cohen, Annette Mathew, Kirk D. Dourvetakis, Estella Sanchez-Guerrero, Rajendra P. Pangeni, Narasimman Gurusamy, Kristina K. Aenlle, Geeta Ravindran, Assma Twahir, Dylan Isler, Sara Rukmini Sosa-Garcia, Axel Llizo, Alison C. Bested, Theoharis C. Theoharides, Nancy G. Klimas and Duraisamy Kempuraj
Cells 2024, 13(6), 511; https://doi.org/10.3390/cells13060511 - 14 Mar 2024
Viewed by 2625
Abstract
Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders [...] Read more.
Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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21 pages, 769 KiB  
Review
Th17 Cells, Glucocorticoid Resistance, and Depression
by Julia N. Khantakova, Anastasia Mutovina, Kseniya A. Ayriyants and Natalia P. Bondar
Cells 2023, 12(23), 2749; https://doi.org/10.3390/cells12232749 - 30 Nov 2023
Cited by 3 | Viewed by 1425
Abstract
Depression is a severe mental disorder that disrupts mood and social behavior and is one of the most common neuropsychological symptoms of other somatic diseases. During the study of the disease, a number of theories were put forward (monoamine, inflammatory, vascular theories, etc.), [...] Read more.
Depression is a severe mental disorder that disrupts mood and social behavior and is one of the most common neuropsychological symptoms of other somatic diseases. During the study of the disease, a number of theories were put forward (monoamine, inflammatory, vascular theories, etc.), but none of those theories fully explain the pathogenesis of the disease. Steroid resistance is a characteristic feature of depression and can affect not only brain cells but also immune cells. T-helper cells 17 type (Th17) are known for their resistance to the inhibitory effects of glucocorticoids. Unlike the inhibitory effect on other subpopulations of T-helper cells, glucocorticoids can enhance the differentiation of Th17 lymphocytes, their migration to the inflammation, and the production of IL-17A, IL-21, and IL-23 in GC-resistant disease. According to the latest data, in depression, especially the treatment-resistant type, the number of Th17 cells in the blood and the production of IL-17A is increased, which correlates with the severity of the disease. However, there is still a significant gap in knowledge regarding the exact mechanisms by which Th17 cells can influence neuroinflammation in depression. In this review, we discuss the mutual effect of glucocorticoid resistance and Th17 lymphocytes on the pathogenesis of depression. Full article
(This article belongs to the Special Issue New Advances in Neuroinflammation)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Imaging glial activation by TSPO in a mouse of chronic inflammation - correlation of [18]F-PBR111 PET imaging and immunohistochemistry
Authors: Garry Niedermayer1, Gita Rahardjo2, Guo-Jun Liu2,3, Arvind Parmar2, Rashmi Gamage4, Min-je Hwang1, Monokesh Sen4,5, Gerald Münch4 , Erika Gyengesi4
Affiliation: 1 School of Science, Western Sydney University, Penrith, NSW, 2751 Australia 2 Australian Nuclear Science and Technology Organization, Kirrawee DC, NSW, 2232, Australia 3 Medical Imaging, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia 4 Pharmacology Unit, School of Medicine, Western Sydney University, Penrith, NSW, 2751, NSW, Australia 5 University of Sydney, Sydney, NSW, Australia
Abstract: Chronic neuroinflammation is a confirmed contributing factor to many neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s disease, amongst many other. Potential therapeutic development would hugely benefit from positron emission tomography (PET) imaging with non-invasive translatable biomarker, not only to track the disease progression but also to monitor the response for treatment. One of the potential methods to monitor neuroinflammation in vivo is PET imaging, using a radiotracer binding to the translocator protein 18 kDa (TSPO) [18]F-PBR111 to detect (micro)glial activation. Wild type (C57BL/6) and GFAP-IL6 (mouse model of chronic neuroinflammation) mice were used to validate the TSPO biomarker in a PET/CT study and correlate the TSPO PET images with immunohistochemical images using a TSPO antibody. The PET/CT study was performed in a cohort of 5-month-old mice (GFAP-IL6 (n=5) and C57Bl/6 wild type (n=5)). A one-hour dynamic PET/CT scan was performed using the TSPO radioligand [18]F-PBR111, followed by autoradiography and immunohistochemical analysis. There was a statistically significant increase of in 18F-PBR111 binding in the cerebellum of the GFAP-IL6 mice group compared to the wild type mice group. Our results have further validated the GFAP-IL6 mice model as a potential candidate to study gliosis and neuroinflammation both in vivo and in vitro. Furthermore, PET/CT imaging using [18]F-PBR11 may be utilized to study the effect of potential drug candidates to treat or possibly prevent neuroinflammation in this mouse model.

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