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Microglia in Neurological Diseases
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Microglia in Neurological Diseases

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

Deadline for manuscript submissions: 15 May 2024 | Viewed by 14859

Special Issue Editors

Prof. Dr. Kate Lykke Lambertsen

E-Mail Website
Guest Editor
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark
Interests: neuroinflammation; microglia; cytokines; stroke; spinal cord injury
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bente Finsen

E-Mail Website
Guest Editor
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
Interests: neurobiology

Special Issue Information

Dear Colleagues,

Microglia colonize the CNS in early embryogenesis and are established by birth as an autonomously maintained population for the lifetime of the host. These glial cells fulfil tissue homeostasis functions and recently there has been an explosion in new findings giving us insight into the involvement of microglia in CNS disorders. A host of new molecular tools and mouse models of disease are increasingly implicating microglia as a key player in conditions ranging from neurodevelopmental disorders, expressing functional phenotypes sculpting developing neuronal circuits and guiding learning-associated plasticity; to neuroinflammatory and neurodegenerative disorders, where microglia progressively change their functional capability. Although much still needs to be learned, the emerging picture is that microglia can be both protective and detrimental, and understanding the physiological functions of these cells is crucial to determining their roles in disease.

The goal of this Special Issue is to provide a panorama of the ongoing efforts in elucidating the functions of microglia in neurological disease. We aim to cover a wide range of pathologies, including developmental pathologies and those ranging from traumatic to classically inflammatory and degenerative.

We look forward to your contributions.

Prof. Dr. Kate Lykke Lambertsen
Prof. Dr. Bente Finsen
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.

Published Papers (6 papers)

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Research

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16 pages, 3908 KiB  
Article
miR-154-5p Is a Novel Endogenous Ligand for TLR7 Inducing Microglial Activation and Neuronal Injury
by Hugo McGurran, Victor Kumbol, Christina Krüger, Thomas Wallach and Seija Lehnardt
Cells 2024, 13(5), 407; https://doi.org/10.3390/cells13050407 - 26 Feb 2024
Cited by 1 | Viewed by 742
Abstract
Toll-like receptors (TLRs) are a collection of pattern recognition sensors that form a first line of defence by detecting pathogen- or damage-associated molecular patterns and initiating an inflammatory response. TLR activation in microglia, the major immune cells in the brain, can trigger the [...] Read more.
Toll-like receptors (TLRs) are a collection of pattern recognition sensors that form a first line of defence by detecting pathogen- or damage-associated molecular patterns and initiating an inflammatory response. TLR activation in microglia, the major immune cells in the brain, can trigger the release of inflammatory molecules, which may contribute to various CNS diseases including Alzheimer’s disease. Recently, some microRNAs were shown to serve as signalling molecules for TLRs. Here, we present miR-154-5p as a novel TLR7 ligand. Exposing microglia to miR-154-5p results in cytokine release and alters expression of the TLR signalling pathway dependent on TLR7. Additionally, miR-154-5p causes neuronal injury in enriched cortical neuron cultures and additive toxicity in the presence of microglia. Finally, intrathecal injection of miR-154-5p into mice leads to neuronal injury and accumulation of microglia in the cerebral cortex dependent on TLR7 expression. In conclusion, this study establishes miR-154-5p as a direct activator of TLR7 that can cause neuroinflammation and neuronal injury, which may contribute to CNS disease. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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12 pages, 3035 KiB  
Article
Microglia-Derived Insulin-like Growth Factor 1 Is Critical for Neurodevelopment
by Dominika Rusin, Lejla Vahl Becirovic, Gabriela Lyszczarz, Martin Krueger, Anouk Benmamar-Badel, Cecilie Vad Mathiesen, Eydís Sigurðardóttir Schiöth, Kate Lykke Lambertsen and Agnieszka Wlodarczyk
Cells 2024, 13(2), 184; https://doi.org/10.3390/cells13020184 - 18 Jan 2024
Viewed by 1063
Abstract
Insulin-like growth factor 1 (IGF-1) is a peptide hormone essential for the proper development and growth of the organism, as a complete knockout of Igf1 in mice is lethal, causing microcephaly, growth retardation and the defective development of organs. In the central nervous [...] Read more.
Insulin-like growth factor 1 (IGF-1) is a peptide hormone essential for the proper development and growth of the organism, as a complete knockout of Igf1 in mice is lethal, causing microcephaly, growth retardation and the defective development of organs. In the central nervous system, neurons and glia have been reported to express Igf1, but their relative importance for postnatal development has not yet been fully defined. In order to address this, here, we obtained mice with a microglia-specific inducible conditional knockout of Igf1. We show that the deficiency in microglial Igf1, starting in the first postnatal week, leads to body and brain growth retardation, severely impaired myelination, changes in microglia numbers, and behavioral abnormalities. These results emphasize the importance of microglial-derived Igf1 for brain development and function and open new perspectives for the investigation of the role of microglial-Igf1 in neurological diseases. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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31 pages, 7464 KiB  
Article
The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia
by Elliot J. Glotfelty, Luis B. Tovar-y-Romo, Shih-Chang Hsueh, David Tweedie, Yazhou Li, Brandon K. Harvey, Barry J. Hoffer, Tobias E. Karlsson, Lars Olson and Nigel H. Greig
Cells 2023, 12(10), 1367; https://doi.org/10.3390/cells12101367 - 11 May 2023
Cited by 4 | Viewed by 3931
Abstract
Neuroinflammation is a unifying factor among all acute central nervous system (CNS) injuries and chronic neurodegenerative disorders. Here, we used immortalized microglial (IMG) cells and primary microglia (PMg) to understand the roles of the GTPase Ras homolog gene family member A (RhoA) and [...] Read more.
Neuroinflammation is a unifying factor among all acute central nervous system (CNS) injuries and chronic neurodegenerative disorders. Here, we used immortalized microglial (IMG) cells and primary microglia (PMg) to understand the roles of the GTPase Ras homolog gene family member A (RhoA) and its downstream targets Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) in neuroinflammation. We used a pan-kinase inhibitor (Y27632) and a ROCK1- and ROCK2-specific inhibitor (RKI1447) to mitigate a lipopolysaccharide (LPS) challenge. In both the IMG cells and PMg, each drug significantly inhibited pro-inflammatory protein production detected in media (TNF-α, IL-6, KC/GRO, and IL-12p70). In the IMG cells, this resulted from the inhibition of NF-κB nuclear translocation and the blocking of neuroinflammatory gene transcription (iNOS, TNF-α, and IL-6). Additionally, we demonstrated the ability of both compounds to block the dephosphorylation and activation of cofilin. In the IMG cells, RhoA activation with Nogo-P4 or narciclasine (Narc) exacerbated the inflammatory response to the LPS challenge. We utilized a siRNA approach to differentiate ROCK1 and ROCK2 activity during the LPS challenges and showed that the blockade of both proteins may mediate the anti-inflammatory effects of Y27632 and RKI1447. Using previously published data, we show that genes in the RhoA/ROCK signaling cascade are highly upregulated in the neurodegenerative microglia (MGnD) from APP/PS-1 transgenic Alzheimer’s disease (AD) mice. In addition to illuminating the specific roles of RhoA/ROCK signaling in neuroinflammation, we demonstrate the utility of using IMG cells as a model for primary microglia in cellular studies. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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16 pages, 2508 KiB  
Article
Anti-Inflammatory Properties of the SGLT2 Inhibitor Empagliflozin in Activated Primary Microglia
by Marvin Heimke, Florian Lenz, Uta Rickert, Ralph Lucius and François Cossais
Cells 2022, 11(19), 3107; https://doi.org/10.3390/cells11193107 - 02 Oct 2022
Cited by 11 | Viewed by 2670
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, are routinely used as antidiabetic drugs. Recent studies indicate that beside its beneficial effects on blood glucose level, empagliflozin may also exert vascular anti-inflammatory and neuroprotective properties. In the brain, microglia are crucial mediators of inflammation, [...] Read more.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, are routinely used as antidiabetic drugs. Recent studies indicate that beside its beneficial effects on blood glucose level, empagliflozin may also exert vascular anti-inflammatory and neuroprotective properties. In the brain, microglia are crucial mediators of inflammation, and neuroinflammation plays a key role in neurodegenerative disorders. Dampening microglia-mediated inflammation may slow down disease progression. In this context, we investigated the immunomodulatory effect of empagliflozin on activated primary microglia. As a validated experimental model, rat primary microglial cells were activated into a pro-inflammatory state by stimulation with LPS. The influence of empagliflozin on the expression of pro-inflammatory mediators (NO, Nos2, IL6, TNF, IL1B) and on the anti-inflammatory mediator IL10 was assessed using quantitative PCR and ELISA. Further, we investigated changes in the activation of the ERK1/2 cascade by Western blot and NFkB translocation by immunostaining. We observed that empagliflozin reduces the expression of pro- and anti-inflammatory mediators in LPS-activated primary microglia. These effects might be mediated by NHE-1, rather than by SGLT2, and by the further inhibition of the ERK1/2 and NFkB pathways. Our results support putative anti-inflammatory effects of empagliflozin on microglia and suggest that SGLT2 inhibitors may exert beneficial effects in neurodegenerative disorders. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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Review

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22 pages, 2950 KiB  
Review
Cross-Talk and Subset Control of Microglia and Associated Myeloid Cells in Neurological Disorders
by Jatia Mills, Liliana Ladner, Eman Soliman, John Leonard, Paul D. Morton and Michelle H. Theus
Cells 2022, 11(21), 3364; https://doi.org/10.3390/cells11213364 - 25 Oct 2022
Cited by 4 | Viewed by 2621
Abstract
Neurological disorders are highly prevalent and often lead to chronic debilitating disease. Neuroinflammation is a major driver across the spectrum of disorders, and microglia are key mediators of this response, gaining wide acceptance as a druggable cell target. Moreover, clinical providers have limited [...] Read more.
Neurological disorders are highly prevalent and often lead to chronic debilitating disease. Neuroinflammation is a major driver across the spectrum of disorders, and microglia are key mediators of this response, gaining wide acceptance as a druggable cell target. Moreover, clinical providers have limited ability to objectively quantify patient-specific changes in microglia status, which can be a predictor of illness and recovery. This necessitates the development of diagnostic biomarkers and imaging techniques to monitor microglia-mediated neuroinflammation in coordination with neurological outcomes. New insights into the polarization status of microglia have shed light on the regulation of disease progression and helped identify a modifiable target for therapeutics. Thus, the detection and monitoring of microglia activation through the inclusion of diagnostic biomarkers and imaging techniques will provide clinical tools to aid our understanding of the neurologic sequelae and improve long-term clinical care for patients. Recent achievements demonstrated by pre-clinical studies, using novel depletion and cell-targeted approaches as well as single-cell RNAseq, underscore the mechanistic players that coordinate microglial activation status and offer a future avenue for therapeutic intervention. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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17 pages, 13511 KiB  
Review
Loss of Homeostatic Microglia Signature in Prion Diseases
by Yue Wang, Kristin Hartmann, Edda Thies, Behnam Mohammadi, Hermann Altmeppen, Diego Sepulveda-Falla, Markus Glatzel and Susanne Krasemann
Cells 2022, 11(19), 2948; https://doi.org/10.3390/cells11192948 - 21 Sep 2022
Cited by 3 | Viewed by 2536
Abstract
Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrPC), into its disease-associated [...] Read more.
Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrPC), into its disease-associated isoform PrPSc. Besides the aggregation and deposition of misfolded PrPSc, prion diseases are characterized by spongiform lesions and the activation of astrocytes and microglia. Microglia are the innate immune cells of the brain. Activated microglia and astrocytes represent a common pathological feature in neurodegenerative disorders. The role of activated microglia has already been studied in prion disease mouse models; however, it is still not fully clear how they contribute to disease progression. Moreover, the role of microglia in human prion diseases has not been thoroughly investigated thus far, and specific molecular pathways are still undetermined. Here, we review the current knowledge on the different roles of microglia in prion pathophysiology. We discuss microglia markers that are also dysregulated in other neurodegenerative diseases including microglia homeostasis markers. Data on murine and human brain tissues show that microglia are highly dysregulated in prion diseases. We highlight here that the loss of homeostatic markers may especially stand out. Full article
(This article belongs to the Special Issue Microglia in Neurological Diseases)
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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: Microglia-derived extracellular vesicles enhance oligodendro-cyte maturation by transcriptionally regulating mitochondrial molecular pathways
Authors: Stefano Raffaele 1, Marta Lombardi 2, Claudia Verderio 2 and Marta Fumagalli 1,*
Affiliation: 1 Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy 2 CNR Institute of Neuroscience, Vedano al Lambro, MB, 20854, Italy
Abstract: Abstract (Max 200 words): Degeneration of myelinating oligodendrocytes (OLs) and consequent disruption of the myelin sheath enwrapping neuronal axons represent major contributing factors to neurodegeneration and disability in several neuropathological conditions. Fostering endog-enous myelin repair sustained by oligodendrocyte precursor cells (OPCs) is therefore considered a promising therapeutic approach to preserve neuronal integrity and to counteract disease pro-gression. A central role in shaping remyelination is played by microglia, that influence both myelin damage and repair processes by acquiring different functional states. In this respect, ex-tracellular vesicles (EVs) released by microglia emerged as pivotal players in the communication with OPCs. Our recent studies show that EVs derived from pro-regenerative microglia efficiently enhanced OPC maturation and remyelination in different experimental settings. However, the mechanisms underlying EV-induced beneficial effects on OPCs still need to be elucidated. Here, we performed a transcriptomic profiling of primary OPCs exposed to either pro-inflammatory (i-EVs) or pro-regenerative (IL4-EVs and MSC-EVs) microglial EVs, revealing prominent changes induced by protective types of EVs compared to untreated cells (CTRL), while i-EVs were less potent. Bi-oinformatic tools have been exploited to identify the molecular pathways significantly modulated by EVs in recipient OPCs, showing that most of them were in common between IL4-EVs and MSC-EVs, and to predict the upstream regulators that might be responsible for these transcrip-tional changes. Results suggest that rewiring of mitochondria-associated molecular pathways in OPCs underpins the pro-differentiating action of microglial EVs, opening novel perspectives for remyelinating therapies.

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