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Molecular, Cellular and Systemic Signature of Microglia
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Molecular, Cellular and Systemic Signature of Microglia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 79009

Special Issue Editors

Prof. Dr. Markus Ritter

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Guest Editor
Institute for Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
Interests: microglial; cancer stem cell; chloride current
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hubert H. Kerschbaum

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Co-Guest Editor
Department of Cell Biology, University of Salzburg, 5020 Salzburg, Austria
Interests: microglial; cancer stem cell; chloride current
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

How do microglia, the innate immune cells of the central nervous system, shape the structure and function of the central nervous system? What happens when the neural environment changes due to an injury or microbial neuroinvasion? How do microglia communicate with astrocytes and neurons? Since the state of microglia is vital for the health of neural cells, answers to these questions are indispensable for understanding the (patho)physiology of the brain.

The structural phenotype of microglia reflects their functional state. The ramified phenotype, surveilling its environment in the healthy brain, transforms upon rupture of capillaries or microbial neuroinvasion into an amoeboid phagocyte, boosting the clearance of cell debris. While pruning of a surplus of synapses by microglia is physiological in early development, it may become pathophysiological in the adult brain, thus driving neurodegeneration.

Experimental evidence strongly points to the involvement of microglia in a diversity of neural functions, including the development of the brain, learning, neuroinflammation, fighting neuroinvasive microbes, and neurodegeneration. Reviews and original research papers presented in this Special Issue will provide an overview of the current state-of-the-art microglia research from all biomedical fields.

Prof. Dr. Markus Ritter
Prof. Dr. Hubert H. Kerschbaum
Guest Editor

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Published Papers (16 papers)

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Research

Jump to: Review

26 pages, 5689 KiB  
Article
The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice
by Johanna Michael, Julia Zirknitzer, Michael Stefan Unger, Rodolphe Poupardin, Tanja Rieß, Nadine Paiement, Horst Zerbe, Birgit Hutter-Paier, Herbert Reitsamer and Ludwig Aigner
Int. J. Mol. Sci. 2021, 22(5), 2782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052782 - 09 Mar 2021
Cited by 16 | Viewed by 4429
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling—more [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling—more specifically, the leukotriene receptors—has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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17 pages, 3395 KiB  
Article
The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory
by Trim Lajqi, Christian Marx, Hannes Hudalla, Fabienne Haas, Silke Große, Zhao-Qi Wang, Regine Heller, Michael Bauer, Reinhard Wetzker and Reinhard Bauer
Int. J. Mol. Sci. 2021, 22(5), 2578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052578 - 04 Mar 2021
Cited by 13 | Viewed by 2867
Abstract
Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose [...] Read more.
Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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26 pages, 2683 KiB  
Article
Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia
by Lisha Joshi, Ioanna Plastira, Eva Bernhart, Helga Reicher, Chintan N. Koyani, Tobias Madl, Corina Madreiter-Sokolowski, Zhanat Koshenov, Wolfgang F. Graier, Seth Hallström and Wolfgang Sattler
Int. J. Mol. Sci. 2021, 22(4), 1968; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041968 - 17 Feb 2021
Cited by 10 | Viewed by 3357
Abstract
Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and [...] Read more.
Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and can display beneficial or detrimental effects on microglia function. During earlier studies we reported that LPA treatment of microglia induces polarization towards a neurotoxic phenotype. In the present study we investigated whether these alterations are accompanied by the induction of a specific immunometabolic phenotype in LPA-treated BV-2 microglia. In response to LPA (1 µM) we observed slightly decreased mitochondrial respiration, increased lactate secretion and reduced ATP/ADP ratios indicating a switch towards aerobic glycolysis. Pathway analyses demonstrated induction of the Akt-mTOR-Hif1α axis under normoxic conditions. LPA treatment resulted in dephosphorylation of AMP-activated kinase, de-repression of acetyl-CoA-carboxylase and increased fatty acid content in the phospholipid and triacylglycerol fraction of BV-2 microglia lipid extracts, indicating de novo lipogenesis. LPA led to increased intracellular amino acid content at one or more time points. Finally, we observed LPA-dependent generation of reactive oxygen species (ROS), phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2), upregulated protein expression of the Nrf2 target regulatory subunit of glutamate-cysteine ligase and increased glutathione synthesis. Our observations suggest that LPA, as a bioactive lipid, induces subtle alterations of the immunometabolic program in BV-2 microglia. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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23 pages, 7463 KiB  
Article
The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model
by Przemyslaw Wielgat, Natalia Wawrusiewicz-Kurylonek, Robert Czarnomysy, Karol Rogowski, Krzysztof Bielawski and Halina Car
Int. J. Mol. Sci. 2021, 22(4), 1791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041791 - 11 Feb 2021
Cited by 7 | Viewed by 2200
Abstract
The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid—Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms [...] Read more.
The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid—Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient’s phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient’s therapy plan verification. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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15 pages, 4660 KiB  
Article
Comparative Analysis Identifies Similarities between the Human and Murine Microglial Sensomes
by Erik R. Abels, Lisa Nieland, Suzanne Hickman, Marike L. D. Broekman, Joseph El Khoury and Sybren L. N. Maas
Int. J. Mol. Sci. 2021, 22(3), 1495; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031495 - 02 Feb 2021
Cited by 19 | Viewed by 3432
Abstract
One of the essential functions of microglia is to continuously sense changes in their environment and adapt to those changes. For this purpose, they use a set of genes termed the sensome. This sensome is comprised of the most abundantly expressed receptors on [...] Read more.
One of the essential functions of microglia is to continuously sense changes in their environment and adapt to those changes. For this purpose, they use a set of genes termed the sensome. This sensome is comprised of the most abundantly expressed receptors on the surface of microglia. In this study, we updated previously identified mouse microglial sensome by incorporating an additional published RNAseq dataset into the data-analysis pipeline. We also identified members of the human microglial sensome using two independent human microglia RNAseq data sources. Using both the mouse and human microglia sensomes, we identified a key set of genes conserved between the mouse and human microglial sensomes as well as some differences between the species. We found a key set of 57 genes to be conserved in both mouse and human microglial sensomes. We define these genes as the “microglia core sensome”. We then analyzed expression of genes in this core sensome in five different datasets from two neurodegenerative disease models at various stages of the diseases and found that, overall, changes in the level of expression of microglial sensome genes are specific to the disease or condition studied. Our results highlight the relevance of data generated in mice for understanding the biology of human microglia, but also stress the importance of species-specific gene sets for the investigation of diseases involving microglia. Defining this microglial specific core sensome may help identify pathological changes in microglia in humans and mouse models of human disease. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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20 pages, 3528 KiB  
Article
Dissection of P2X4 and P2X7 Receptor Current Components in BV-2 Microglia
by Mira Trang, Günther Schmalzing, Christa E. Müller and Fritz Markwardt
Int. J. Mol. Sci. 2020, 21(22), 8489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228489 - 11 Nov 2020
Cited by 17 | Viewed by 2754
Abstract
Microglia cells represent the immune system of the central nervous system. They become activated by ATP released from damaged and inflamed tissue via purinergic receptors. Ionotropic purinergic P2X4 and P2X7 receptors have been shown to be involved in neurological inflammation and pain sensation. [...] Read more.
Microglia cells represent the immune system of the central nervous system. They become activated by ATP released from damaged and inflamed tissue via purinergic receptors. Ionotropic purinergic P2X4 and P2X7 receptors have been shown to be involved in neurological inflammation and pain sensation. Whether the two receptors assemble exclusively as homotrimers or also as heterotrimers is still a matter of debate. We investigated the expression of P2X receptors in BV-2 microglia cells applying the whole-cell voltage-clamp technique. We dissected P2X4 and P2X7 receptor-mediated current components by using specific P2X4 and P2X7 receptor blockers and by their characteristic current kinetics. We found that P2X4 and P2X7 receptors are activated independently from each other, indicating that P2X4/P2X7 heteromers are not of functional significance in these cells. The pro-inflammatory mediators lipopolysaccharide and interferon γ, if applied in combination, upregulated P2X4, but not P2X7 receptor-dependent current components also arguing against phenotypically relevant heteromerization of P2X4 and P2X7 receptor subunits. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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22 pages, 4491 KiB  
Article
PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation
by Marta Chiavari, Gabriella Maria Pia Ciotti, Francesco Canonico, Fabio Altieri, Pedro Miguel Lacal, Grazia Graziani, Pierluigi Navarra and Lucia Lisi
Int. J. Mol. Sci. 2020, 21(21), 8214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218214 - 03 Nov 2020
Cited by 25 | Viewed by 3612
Abstract
The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the [...] Read more.
The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia–glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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20 pages, 4896 KiB  
Article
Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations
by Daniele Mattei, Andranik Ivanov, Marc van Oostrum, Stanislav Pantelyushin, Juliet Richetto, Flavia Mueller, Michal Beffinger, Linda Schellhammer, Johannes vom Berg, Bernd Wollscheid, Dieter Beule, Rosa Chiara Paolicelli and Urs Meyer
Int. J. Mol. Sci. 2020, 21(21), 7944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217944 - 26 Oct 2020
Cited by 57 | Viewed by 6706
Abstract
Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of [...] Read more.
Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37 °C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4 °C. These findings emphasize the risk of introducing technical biases and biological artifacts when implementing enzymatic digestion-based isolation methods for brain cell analyses. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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15 pages, 4562 KiB  
Article
Activation of Adenosine A3 Receptor Inhibits Microglia Reactivity Elicited by Elevated Pressure
by Joana Ferreira-Silva, Inês D. Aires, Raquel Boia, António Francisco Ambrósio and Ana Raquel Santiago
Int. J. Mol. Sci. 2020, 21(19), 7218; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197218 - 30 Sep 2020
Cited by 13 | Viewed by 2367
Abstract
Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness, characterized by optic nerve damage and retinal ganglion cell (RGC) death. Elevated intraocular pressure (IOP) is a main risk factor of glaucoma. Neuroinflammation plays an important role [...] Read more.
Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness, characterized by optic nerve damage and retinal ganglion cell (RGC) death. Elevated intraocular pressure (IOP) is a main risk factor of glaucoma. Neuroinflammation plays an important role in glaucoma. We have been demonstrating that elevated pressure triggers microglia reactivity that contribute to the loss of RGCs. Adenosine, acting on adenosine receptors, is a crucial modulator of microglia phenotype. Microglia express all adenosine receptors. Previously, we demonstrated that the activation of adenosine A3 receptor (A3R) affords protection to the retina, including RGCs, unveiling the possibility for a new strategy for glaucoma treatment. Since microglial cells express A3R, we now studied the ability of a selective A3R agonist (2-Cl-IB-MECA) in controlling microglia reactivity induced by elevated hydrostatic pressure (EHP), used to mimic elevated IOP. The activation of A3R reduced EHP-induced inducible nitric oxide synthase (iNOS) expression, microglia migration and phagocytosis in BV-2 cells. In retinal microglia, proliferation and phagocytosis elicited by EHP were also decreased by A3R activation. This work demonstrates that 2-Cl-IB-MECA, the selective agonist of A3R, is able to hinder microglia reactivity, suggesting that A3R agonists could afford protection against glaucomatous degeneration through the control of neuroinflammation. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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Review

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19 pages, 508 KiB  
Review
Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?
by Anastasia Geladaris, Darius Häusler and Martin S. Weber
Int. J. Mol. Sci. 2021, 22(7), 3461; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073461 - 27 Mar 2021
Cited by 21 | Viewed by 7568
Abstract
Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. [...] Read more.
Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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36 pages, 24027 KiB  
Review
Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
by Mehdi Eshraghi, Aida Adlimoghaddam, Amir Mahmoodzadeh, Farzaneh Sharifzad, Hamed Yasavoli-Sharahi, Shahrokh Lorzadeh, Benedict C. Albensi and Saeid Ghavami
Int. J. Mol. Sci. 2021, 22(7), 3330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073330 - 24 Mar 2021
Cited by 71 | Viewed by 11212
Abstract
Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, [...] Read more.
Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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22 pages, 3419 KiB  
Review
Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases
by Jagdeep K. Sandhu and Marianna Kulka
Int. J. Mol. Sci. 2021, 22(3), 1093; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031093 - 22 Jan 2021
Cited by 38 | Viewed by 5386
Abstract
Microglia, resident immune cells of the central nervous system (CNS), play a pivotal role in immune surveillance and maintenance of neuronal health. Mast cells are also important resident immune cells of the CNS but they are underappreciated and understudied. Both microglia and mast [...] Read more.
Microglia, resident immune cells of the central nervous system (CNS), play a pivotal role in immune surveillance and maintenance of neuronal health. Mast cells are also important resident immune cells of the CNS but they are underappreciated and understudied. Both microglia and mast cells are endowed with an array of signaling receptors that recognize microbes and cellular damage. As cellular sensors and effectors in the CNS, they respond to many CNS perturbations and have been implicated in neuroinflammation and neurodegeneration. Mast cells contain numerous secretory granules packaged with a plethora of readily available and newly synthesized compounds known as ‘mast cell mediators’. Mast cells act as ‘first responders’ to a pathogenic stimuli and respond by degranulation and releasing these mediators into the extracellular milieu. They alert other glial cells, including microglia to initiate neuroinflammatory processes that culminate in the resolution of injury. However, failure to resolve the pathogenic process can lead to persistent activation, release of pro-inflammatory mediators and amplification of neuroinflammatory responses, in turn, resulting in neuronal dysfunction and demise. This review discusses the current understanding of the molecular conversation between mast cells and microglia in orchestrating immune responses during two of the most prevalent neurodegenerative diseases, namely Alzheimer’s disease and Parkinson’s disease. Here we also survey the potential emerging therapeutic approaches targeting common pathways in mast cells and microglia to extinguish the fire of inflammation. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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21 pages, 13394 KiB  
Review
Changing Functional Signatures of Microglia along the Axis of Brain Aging
by Bianca Brawek, Maryna Skok and Olga Garaschuk
Int. J. Mol. Sci. 2021, 22(3), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031091 - 22 Jan 2021
Cited by 18 | Viewed by 4209
Abstract
Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages. [...] Read more.
Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages. Indeed, microglia adapt exceptionally well to their microenvironment, becoming a legitimate member of the cellular brain architecture. The ramified or surveillant microglia in the young adult brain are characterized by specific morphology (small cell body and long, thin motile processes) and physiology (a unique pattern of Ca2+ signaling, responsiveness to various neurotransmitters and hormones, in addition to classic “immune” stimuli). Their numerous physiological functions far exceed and complement their immune capabilities. As the brain ages, the respective changes in the microglial microenvironment impact the functional properties of microglia, triggering further rounds of adaptation. In this review, we discuss the recent data showing how functional properties of microglia adapt to age-related changes in brain parenchyma in a sex-specific manner, with a specific focus on early changes occurring at middle age as well as some strategies counteracting the aging of microglia. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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27 pages, 1685 KiB  
Review
Little Helpers or Mean Rogue—Role of Microglia in Animal Models of Amyotrophic Lateral Sclerosis
by Hilal Cihankaya, Carsten Theiss and Veronika Matschke
Int. J. Mol. Sci. 2021, 22(3), 993; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22030993 - 20 Jan 2021
Cited by 8 | Viewed by 3678
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, causing degeneration of both upper and lower motor neurons in the central nervous system (CNS). ALS patients suffer from hyperreflexia, spasticity, paralysis and muscle atrophy and typically die due to respiratory [...] Read more.
Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, causing degeneration of both upper and lower motor neurons in the central nervous system (CNS). ALS patients suffer from hyperreflexia, spasticity, paralysis and muscle atrophy and typically die due to respiratory failure 1–5 years after disease onset. In addition to the degeneration of motor neurons on the cellular level, ALS has been associated with neuroinflammation, such as microgliosis. Microglial activation in ALS can either be protective or degenerative to the neurons. Among others, mutations in superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9Orf72), transactive response DNA binding protein (TDP) 43 and vacuolar protein sorting-associated protein 54 (VPS54) genes have been associated with ALS. Here, we describe the dual role and functionality of microglia in four different in vivo ALS models and search for the lowest common denominator with respect to the role of microglia in the highly heterogeneous disease of ALS. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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18 pages, 692 KiB  
Review
Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?
by Susan Brandenburg, Anne Blank, Alexander D. Bungert and Peter Vajkoczy
Int. J. Mol. Sci. 2021, 22(1), 194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010194 - 27 Dec 2020
Cited by 32 | Viewed by 6242
Abstract
For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the [...] Read more.
For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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24 pages, 2143 KiB  
Review
Germinal Matrix-Intraventricular Hemorrhage of the Preterm Newborn and Preclinical Models: Inflammatory Considerations
by Isabel Atienza-Navarro, Pilar Alves-Martinez, Simon Lubian-Lopez and Monica Garcia-Alloza
Int. J. Mol. Sci. 2020, 21(21), 8343; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218343 - 06 Nov 2020
Cited by 24 | Viewed by 7973
Abstract
The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most important complications of the preterm newborn. Since these children are born at a critical time in brain development, they can develop short and long term neurological, sensory, cognitive and motor disabilities depending on [...] Read more.
The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most important complications of the preterm newborn. Since these children are born at a critical time in brain development, they can develop short and long term neurological, sensory, cognitive and motor disabilities depending on the severity of the GM-IVH. In addition, hemorrhage triggers a microglia-mediated inflammatory response that damages the tissue adjacent to the injury. Nevertheless, a neuroprotective and neuroreparative role of the microglia has also been described, suggesting that neonatal microglia may have unique functions. While the implication of the inflammatory process in GM-IVH is well established, the difficulty to access a very delicate population has lead to the development of animal models that resemble the pathological features of GM-IVH. Genetically modified models and lesions induced by local administration of glycerol, collagenase or blood have been used to study associated inflammatory mechanisms as well as therapeutic targets. In the present study we review the GM-IVH complications, with special interest in inflammatory response and the role of microglia, both in patients and animal models, and we analyze specific proteins and cytokines that are currently under study as feasible predictors of GM-IVH evolution and prognosis. Full article
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
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