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Recent Advances in Microglia Research

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 7025

Special Issue Editors

Dr. Daniele Lana

E-Mail Website
Guest Editor
Department of Health Sciences, University of Florence, 50139 Florence, Italy
Interests: neuropharmacology; neurodegeneration; neuroinflammation; glia; microbiota; neurodegenerative diseases; hippocampus; behaviour
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Grazia Giovannini

E-Mail Website
Guest Editor
Department of Health Sciences, University of Florence, 50139 Florence, Italy
Interests: neuroinflammation; memory; aging; cholinergic system; Alzheimer’s disease; hippocampus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Microglia, the primary immune cells of the central nervous system, have very mobile ramified branches that dynamically and continuously survey brain parenchyma to detect and eliminate debris of damaged neurons by phagocytosis and to restore tissue homeostasis.. Microglia actively maintain their protective role during normal aging, but this ability is considerably decreased in a proinflammatory context. In animal models of AD, the phagocytic activity and clearance capacity of microglia are inversely correlated with Aβ plaque deposition and aging.

Microglia are plastic cells that undergo profound functional reprogramming. An oversimplified view recognizes two extremes of profound functional reprogramming in response to cytokines, chemokines and other soluble factors produced by damaged neurons, the classical pro-inflammatory and the anti-inflammatory phenotypes. Between these extreme functional states, a plethora of possible intermediate states is recognized.  Heterogeneity of microglia, either between or within a particular brain region, is likely relevant in healthy conditions and disease processes. Differential crosstalk between microglia, astrocytes and neurons can be responsible for the diverse sensitivity of the different areas to insults. Understanding the spatial differences and roles of microglia will allow for assessing how these interactions can influence the state and progression of diseases and will be critical to identify therapeutic strategies.

The complexity in microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models. In this regard, investigators are invited to contribute to this Special Issue with original research articles and review articles that can improve the understanding of the role of microglia in physiological conditions, in normal brain aging and neurodegenerative disease.

Dr. Daniele Lana
Dr. Maria Grazia Giovannini
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • neurodegeneration
  • inflammation
  • neurodegenerative disease
  • brain aging
  • phagocytosis
  • cytokines
  • chemokines
  • neuron–astrocyte–microglia triad

Published Papers (5 papers)

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Research

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13 pages, 2113 KiB  
Article
Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation
by Assunta Virtuoso, Christos Galanis, Maximilian Lenz, Michele Papa and Andreas Vlachos
Int. J. Mol. Sci. 2024, 25(4), 2346; https://doi.org/10.3390/ijms25042346 - 16 Feb 2024
Viewed by 530
Abstract
Microglia and astrocytes are essential in sustaining physiological networks in the central nervous system, with their ability to remodel the extracellular matrix, being pivotal for synapse plasticity. Recent findings have challenged the traditional view of homogenous glial populations in the brain, uncovering morphological, [...] Read more.
Microglia and astrocytes are essential in sustaining physiological networks in the central nervous system, with their ability to remodel the extracellular matrix, being pivotal for synapse plasticity. Recent findings have challenged the traditional view of homogenous glial populations in the brain, uncovering morphological, functional, and molecular heterogeneity among glial cells. This diversity has significant implications for both physiological and pathological brain states. In the present study, we mechanically induced a Schaffer collateral lesion (SCL) in mouse entorhino–hippocampal slice cultures to investigate glial behavior, i.e., microglia and astrocytes, under metalloproteinases (MMPs) modulation in the lesioned area, CA3, and the denervated region, CA1. We observed distinct response patterns in the microglia and astrocytes 3 days after the lesion. Notably, GFAP-expressing astrocytes showed no immediate changes post-SCL. Microglia responses varied depending on their anatomical location, underscoring the complexity of the hippocampal neuroglial network post-injury. The MMPs inhibitor GM6001 did not affect microglial reactions in CA3, while increasing the number of Iba1-expressing cells in CA1, leading to a withdrawal of their primary branches. These findings highlight the importance of understanding glial regionalization following neural injury and MMPs modulation and pave the way for further research into glia-targeted therapeutic strategies for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Recent Advances in Microglia Research)
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16 pages, 7809 KiB  
Article
TonEBP: A Key Transcription Factor in Microglia Following Intracerebral Hemorrhage Induced-Neuroinflammation
by Ailiyaer Palahati, Yujia Luo, Le Qin, Yuhao Duan, Mi Zhang, Hui Gan and Xuan Zhai
Int. J. Mol. Sci. 2024, 25(3), 1438; https://doi.org/10.3390/ijms25031438 - 24 Jan 2024
Viewed by 746
Abstract
Transcription factors within microglia contribute to the inflammatory response following intracerebral hemorrhage (ICH). Therefore, we employed bioinformatics screening to identify the potential transcription factor tonicity-responsive enhancer-binding protein (TonEBP) within microglia. Inflammatory stimuli can provoke an elevated expression of TonEBP in microglia. Nevertheless, the [...] Read more.
Transcription factors within microglia contribute to the inflammatory response following intracerebral hemorrhage (ICH). Therefore, we employed bioinformatics screening to identify the potential transcription factor tonicity-responsive enhancer-binding protein (TonEBP) within microglia. Inflammatory stimuli can provoke an elevated expression of TonEBP in microglia. Nevertheless, the expression and function of microglial TonEBP in ICH-induced neuroinflammation remain ambiguous. In our recent research, we discovered that ICH instigated an increased TonEBP in microglia in both human and mouse peri-hematoma brain tissues. Furthermore, our results indicated that TonEBP knockdown mitigates lipopolysaccharide (LPS)-induced inflammation and the activation of NF-κB signaling in microglia. In order to more deeply comprehend the underlying molecular mechanisms of how TonEBP modulates the inflammatory response, we sequenced the transcriptomes of TonEBP-deficient cells and sought potential downstream target genes of TonEBP, such as Pellino-1 (PELI1). PELI has been previously reported to mediate nuclear factor-κB (NF-κB) signaling. Through the utilization of CUT & RUN, a dual-luciferase reporter, and qPCR, we confirmed that TonEBP is the transcription factor of Peli1, binding to the Peli1 promoter. In summary, TonEBP may enhance the LPS-induced inflammation and activation of NF-κB signaling via PELI1. Full article
(This article belongs to the Special Issue Recent Advances in Microglia Research)
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17 pages, 3538 KiB  
Article
Coordinated Transcriptional Waves Define the Inflammatory Response of Primary Microglial Culture
by Keren Zohar, Elyad Lezmi, Fanny Reichert, Tsiona Eliyahu, Shlomo Rotshenker, Marta Weinstock and Michal Linial
Int. J. Mol. Sci. 2023, 24(13), 10928; https://doi.org/10.3390/ijms241310928 - 30 Jun 2023
Viewed by 1221
Abstract
The primary role of microglia is to maintain homeostasis by effectively responding to various disturbances. Activation of transcriptional programs determines the microglia’s response to external stimuli. In this study, we stimulated murine neonatal microglial cells with benzoyl ATP (bzATP) and lipopolysaccharide (LPS), and [...] Read more.
The primary role of microglia is to maintain homeostasis by effectively responding to various disturbances. Activation of transcriptional programs determines the microglia’s response to external stimuli. In this study, we stimulated murine neonatal microglial cells with benzoyl ATP (bzATP) and lipopolysaccharide (LPS), and monitored their ability to release pro-inflammatory cytokines. When cells are exposed to bzATP, a purinergic receptor agonist, a short-lived wave of transcriptional changes, occurs. However, only combining bzATP and LPS led to a sustainable and robust response. The transcriptional profile is dominated by induced cytokines (e.g., IL-1α and IL-1β), chemokines, and their membrane receptors. Several abundant long noncoding RNAs (lncRNAs) are induced by bzATP/LPS, including Ptgs2os2, Bc1, and Morrbid, that function in inflammation and cytokine production. Analyzing the observed changes through TNF (Tumor necrosis factor) and NF-κB (nuclear factor kappa light chain enhancer of activated B cells) pathways confirmed that neonatal glial cells exhibit a distinctive expression program in which inflammatory-related genes are upregulated by orders of magnitude. The observed capacity of the microglial culture to activate a robust inflammatory response is useful for studying neurons under stress, brain injury, and aging. We propose the use of a primary neonatal microglia culture as a responsive in vitro model for testing drugs that may interact with inflammatory signaling and the lncRNA regulatory network. Full article
(This article belongs to the Special Issue Recent Advances in Microglia Research)
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Review

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13 pages, 972 KiB  
Review
The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond
by Luana da Silva Chagas and Claudio Alberto Serfaty
Int. J. Mol. Sci. 2024, 25(7), 3819; https://doi.org/10.3390/ijms25073819 - 29 Mar 2024
Viewed by 1423
Abstract
Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability [...] Read more.
Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults. Full article
(This article belongs to the Special Issue Recent Advances in Microglia Research)
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26 pages, 1436 KiB  
Review
Phenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases
by Daniele Lana, Giada Magni, Elisa Landucci, Gary L. Wenk, Domenico Edoardo Pellegrini-Giampietro and Maria Grazia Giovannini
Int. J. Mol. Sci. 2023, 24(18), 13668; https://doi.org/10.3390/ijms241813668 - 05 Sep 2023
Cited by 2 | Viewed by 2323
Abstract
Phenomics, the complexity of microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models to find druggable targets for neurodegenerative disorders. Activation of microglia was long considered detrimental for neuron survival, but more recently it has become [...] Read more.
Phenomics, the complexity of microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models to find druggable targets for neurodegenerative disorders. Activation of microglia was long considered detrimental for neuron survival, but more recently it has become apparent that the real scenario of microglia morphofunctional diversity is far more complex. In this review, we discuss the recent literature on the alterations in microglia phenomics in the hippocampus of animal models of normal brain aging, acute neuroinflammation, ischemia, and neurodegenerative disorders, such as AD. Microglia undergo phenomic changes consisting of transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. The classical subdivision of microglia into M1 and M2, two different, all-or-nothing states is too simplistic, and does not correspond to the variety of phenotypes recently discovered in the brain. We will discuss the phenomic modifications of microglia focusing not only on the differences in microglia reactivity in the diverse models of neurodegenerative disorders, but also among different areas of the brain. For instance, in contiguous and highly interconnected regions of the rat hippocampus, microglia show a differential, finely regulated, and region-specific reactivity, demonstrating that microglia responses are not uniform, but vary significantly from area to area in response to insults. It is of great interest to verify whether the differences in microglia reactivity may explain the differential susceptibility of different brain areas to insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli. Understanding the spatiotemporal heterogeneity of microglia phenomics in health and disease is of paramount importance to find new druggable targets for the development of novel microglia-targeted therapies in different CNS disorders. This will allow interventions in three different ways: (i) by suppressing the pro-inflammatory properties of microglia to limit the deleterious effect of their activation; (ii) by modulating microglia phenotypic change to favor anti-inflammatory properties; (iii) by influencing microglia priming early in the disease process. Full article
(This article belongs to the Special Issue Recent Advances in Microglia Research)
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