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Cells
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Modulating Microglia to Restore Brain Health
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Modulating Microglia to Restore Brain Health

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 20476

Special Issue Editor

Prof. Dr. Tamir Ben-Hur

E-Mail Website
Guest Editor
Hadassah University Hospital and The Hadassah - Hebrew University Faculty of Medicine, Jerusalem, Israel
Interests: stem cells; regenerative medicine; neuroimmunology

Special Issue Information

Dear Colleagues,

Microglia are emerging as key players in the pathogenesis of multiple neuro-degenerative and chronic neuro-inflammatory diseases, such as Alzheimer’s disease, other dementias, and chronic progressive multiple sclerosis. There is accumulating data to suggest the existence of two competing populations of microglia: one of overactivated and neurotoxic microglia which promote the loss of synapses and neurons; the other of neuroprotective, pro-regenerative microglia, which limit disease progression and support a healing brain environment.

Many open issues remain to be answered:

  1. What is the relationship between these two cell populations, and to resting, homeostatic microglia?
  2. Do neurotoxic and neuroprotective microglia emerge from a common cell population, representing marked plasticity? This may open the possibility of therapeutic modulation to switch their phenotype. Alternatively, do they develop from different pre-existing subtypes that need to be targeted differentially?
  3. What are the bilateral relationships between microglia and other brain cells? How do microglia affect the function of neurons and glia, and how do brain cells affect microglial phenotype and function?
  4. How can known and unknown signaling pathways in microglia be manipulated to restore a healthy brain environment?
  5. How does the systemic immune system cross-talk with brain microglia? Specifically, how do peripheral myeloid cells of the innate immune system, and cells of adaptive immunity affect microglial function and brain health in these diseases?
  6. What differs between disease-promoting microglia in neurodegenerative diseases versus disease-promoting microglia in functional brain disorders such as depression?

These questions and others will be the focus of this Special Issue of Cells.

Prof. Tamir Ben-Hur
Guest Editor

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

  • microglia
  • neurotoxicity
  • homeostasis
  • brain repair
  • immune modulation
  • Alzheimer’s disease
  • neurodegeneration
  • multiple sclerosis

Published Papers (6 papers)

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Research

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18 pages, 2874 KiB  
Article
Lysophosphatidic Acid Receptor 5 (LPA5) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro
by Lisha Joshi, Ioanna Plastira, Eva Bernhart, Helga Reicher, Zhanat Koshenov, Wolfgang F. Graier, Nemanja Vujic, Dagmar Kratky, Richard Rivera, Jerold Chun and Wolfgang Sattler
Cells 2022, 11(7), 1071; https://doi.org/10.3390/cells11071071 - 22 Mar 2022
Cited by 4 | Viewed by 2463
Abstract
Systemic inflammation induces alterations in the finely tuned micromilieu of the brain that is continuously monitored by microglia. In the CNS, these changes include increased synthesis of the bioactive lipid lysophosphatidic acid (LPA), a ligand for the six members of the LPA receptor [...] Read more.
Systemic inflammation induces alterations in the finely tuned micromilieu of the brain that is continuously monitored by microglia. In the CNS, these changes include increased synthesis of the bioactive lipid lysophosphatidic acid (LPA), a ligand for the six members of the LPA receptor family (LPA1-6). In mouse and human microglia, LPA5 belongs to a set of receptors that cooperatively detect danger signals in the brain. Engagement of LPA5 by LPA polarizes microglia toward a pro-inflammatory phenotype. Therefore, we studied the consequences of global LPA5 knockout (-/-) on neuroinflammatory parameters in a mouse endotoxemia model and in primary microglia exposed to LPA in vitro. A single endotoxin injection (5 mg/kg body weight) resulted in lower circulating concentrations of TNFα and IL-1β and significantly reduced gene expression of IL-6 and CXCL2 in the brain of LPS-injected LPA5-/- mice. LPA5 deficiency improved sickness behavior and energy deficits produced by low-dose (1.4 mg LPS/kg body weight) chronic LPS treatment. LPA5-/- microglia secreted lower concentrations of pro-inflammatory cyto-/chemokines in response to LPA and showed higher maximal mitochondrial respiration under basal and LPA-activated conditions, further accompanied by lower lactate release, decreased NADPH and GSH synthesis, and inhibited NO production. Collectively, our data suggest that LPA5 promotes neuroinflammation by transmiting pro-inflammatory signals during endotoxemia through microglial activation induced by LPA. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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20 pages, 5969 KiB  
Article
Failure of Alzheimer’s Mice Brain Resident Neural Precursor Cells in Supporting Microglia-Mediated Amyloid β Clearance
by Marva Lachish, Nina Fainstein, Tal Ganz, Lihi Sofer and Tamir Ben-Hur
Cells 2022, 11(5), 876; https://doi.org/10.3390/cells11050876 - 03 Mar 2022
Cited by 4 | Viewed by 2511
Abstract
The failure of brain microglia to clear excess amyloid β (Aβ) is considered a leading cause of the progression of Alzheimer’s disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have [...] Read more.
The failure of brain microglia to clear excess amyloid β (Aβ) is considered a leading cause of the progression of Alzheimer’s disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have recently showed that resident mouse brain NPCs exhibit an acquired decline in their trophic properties in the Alzheimer’s disease brain environment. Therefore, we hypothesized that functional NPCs may support microglial phagocytic activity, and that NPCs derived from the adult AD mouse brain may fail to support the clearance of Aβ by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high Aβ phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high Aβ phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high Aβ phagocytic activity. Finally, we showed that NPCs also possess the ability to promote Aβ degradation within the microglia with high Aβ phagocytic activity. Thus, resident brain NPCs support microglial function to clear Aβ, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support Aβ clearance from the brain by microglia may accelerate disease pathology. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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17 pages, 3452 KiB  
Article
Involvement of the Microglial Aryl Hydrocarbon Receptor in Neuroinflammation and Vasogenic Edema after Ischemic Stroke
by Miki Tanaka, Masaho Fujikawa, Ami Oguro, Kouichi Itoh, Christoph F. A. Vogel and Yasuhiro Ishihara
Cells 2021, 10(4), 718; https://doi.org/10.3390/cells10040718 - 24 Mar 2021
Cited by 18 | Viewed by 3092
Abstract
Microglia are activated after ischemic stroke and induce neuroinflammation. The expression of the aryl hydrocarbon receptor (AhR) has recently been reported to elicit cytokine expression. We previously reported that microglial activation mediates ischemic edema progression. Thus, the purpose of this study was to [...] Read more.
Microglia are activated after ischemic stroke and induce neuroinflammation. The expression of the aryl hydrocarbon receptor (AhR) has recently been reported to elicit cytokine expression. We previously reported that microglial activation mediates ischemic edema progression. Thus, the purpose of this study was to examine the role of AhR in inflammation and edema after ischemia using a mouse middle cerebral artery occlusion (MCAO) model. MCAO upregulated AhR expression in microglia during ischemia. MCAO increased the expression of tumor necrosis factor α (TNFα) and then induced edema progression, and worsened the modified neurological severity scores, with these being suppressed by administration of an AhR antagonist, CH223191. In THP-1 macrophages, the NADPH oxidase (NOX) subunit p47phox was significantly increased by AhR ligands, especially under inflammatory conditions. Suppression of NOX activity by apocynin or elimination of superoxide by superoxide dismutase decreased TNFα expression, which was induced by the AhR ligand. AhR ligands also elicited p47phox expression in mouse primary microglia. Thus, p47phox may be important in oxidative stress and subsequent inflammation. In MCAO model mice, P47phox expression was upregulated in microglia by ischemia. Lipid peroxidation induced by MCAO was suppressed by CH223191. Taken together, these findings suggest that AhR in the microglia is involved in neuroinflammation and subsequent edema, after MCAO via p47phox expression upregulation and oxidative stress. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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14 pages, 12298 KiB  
Article
Generation of CSF1-Independent Ramified Microglia-Like Cells from Leptomeninges In Vitro
by Junya Tanaka, Hisaaki Takahashi, Hajime Yano and Hiroshi Nakanishi
Cells 2021, 10(1), 24; https://doi.org/10.3390/cells10010024 - 25 Dec 2020
Viewed by 2920
Abstract
Although del Río-Hortega originally reported that leptomeningeal cells are the source of ramified microglia in the developing brain, recent views do not seem to pay much attention to this notion. In this study, in vitro experiments were conducted to determine whether leptomeninges generate [...] Read more.
Although del Río-Hortega originally reported that leptomeningeal cells are the source of ramified microglia in the developing brain, recent views do not seem to pay much attention to this notion. In this study, in vitro experiments were conducted to determine whether leptomeninges generate ramified microglia. The leptomeninges of neonatal rats containing Iba1+ macrophages were peeled off the brain surface. Leptomeningeal macrophages strongly expressed CD68 and CD163, but microglia in the brain parenchyma did not. Leptomeningeal macrophages expressed epidermal growth factor receptor (EGFR) as revealed by RT-PCR and immunohistochemical staining. Cells obtained from the peeled-off leptomeninges were cultured in a serum-free medium containing EGF, resulting in the formation of large cell aggregates in which many proliferating macrophages were present. In contrast, colony-stimulating factor 1 (CSF1) did not enhance the generation of Iba1+ cells from the leptomeningeal culture. The cell aggregates generated ramified Iba1+ cells in the presence of serum, which express CD68 and CD163 at much lower levels than primary microglia isolated from a mixed glial culture. Therefore, the leptomeningeal-derived cells resembled parenchymal microglia better than primary microglia. This study suggests that microglial progenitors expressing EGFR reside in the leptomeninges and that there is a population of microglia-like cells that grow independently of CSF1. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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Review

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22 pages, 1368 KiB  
Review
Central Nervous System Tissue Regeneration after Intracerebral Hemorrhage: The Next Frontier
by Ruiyi Zhang, Mengzhou Xue and Voon Wee Yong
Cells 2021, 10(10), 2513; https://doi.org/10.3390/cells10102513 - 23 Sep 2021
Cited by 18 | Viewed by 3313
Abstract
Despite marked advances in surgical techniques and understanding of secondary brain injury mechanisms, the prognosis of intracerebral hemorrhage (ICH) remains devastating. Harnessing and promoting the regenerative potential of the central nervous system may improve the outcomes of patients with hemorrhagic stroke, but approaches [...] Read more.
Despite marked advances in surgical techniques and understanding of secondary brain injury mechanisms, the prognosis of intracerebral hemorrhage (ICH) remains devastating. Harnessing and promoting the regenerative potential of the central nervous system may improve the outcomes of patients with hemorrhagic stroke, but approaches are still in their infancy. In this review, we discuss the regenerative phenomena occurring in animal models and human ICH, provide results related to cellular and molecular mechanisms of the repair process including by microglia, and review potential methods to promote tissue regeneration in ICH. We aim to stimulate research involving tissue restoration after ICH. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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13 pages, 759 KiB  
Review
Microglia Purinoceptor P2Y6: An Emerging Therapeutic Target in CNS Diseases
by Shehata Anwar, Vincent Pons and Serge Rivest
Cells 2020, 9(7), 1595; https://doi.org/10.3390/cells9071595 - 01 Jul 2020
Cited by 31 | Viewed by 5289
Abstract
The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an “find-me” signal when released in significant quantities by damaged/dying cells. The binding of [...] Read more.
The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an “find-me” signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer’s disease, Parkinson’s disease, radiation-induced brain injury, and neuropathic pain. Full article
(This article belongs to the Special Issue Modulating Microglia to Restore Brain Health)
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