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Cited by 160Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 134 of the 134 references it cites were found in a registry or an index.

Glia Crosstalk in Neuroinflammatory Diseases

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Bernaus, Ada, Blanco, Sandra, Sevilla, Ana·2020·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2020.00209PMC PMC7403442
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Abstract

Neuroinflammation constitutes a fundamental cellular process to signal the loss of brain homeostasis. Glial cells play a central role in orchestrating these neuroinflammation processes in both deleterious and beneficial ways. These cellular responses depend on their intercellular interactions with neurons, astrocytes, the blood-brain barrier (BBB), and infiltrated T cells in the central nervous system (CNS). However, this intercellular crosstalk seems to be activated by specific stimuli for each different neurological scenario. This review summarizes key studies linking neuroinflammation with certain neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) and for the development of better therapeutic strategies based on immunomodulation.

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Figure 1 Neurodegenerative diseases induced by proteinopathies. Specific gene mutations induce proteins to take abnormal structural foldings forming small oligomeric or large fibrillary aggregates. These aggregates precipitate at the intraneuronal and extraneuronal space suffering posttranslational modifications that impair its clearance inducing neuroinflammatory responses.
Figure 1 Neurodegenerative diseases induced by proteinopathies. Specific gene mutations induce proteins to take abnormal structural foldings forming small oligomeric or large fibrillary aggregates. These aggregates precipitate at the intraneuronal and extraneuronal space suffering posttranslational modifications that impair its clearance inducing neuroinflammatory responses.CC BY · PubMed Central
Figure 2 Neuron–microglia crosstalk. An amplification of neuron–microglia interactions is shown in green arrow signals. Homeostatic neurons actively produce anti-inflammatory signals aimed at inhibiting the acquisition of the inflammatory M1-like phenotype by microglial cells. During neurodegenerative disorders or after nervous system injury, cellular mediators associated with damage are activated (salmon arrows) triggering the M1 microglia state that releases reactive species of oxygen and nitrogen (ROS and RNS), glutamate and TNF-α (gray arrows) Importantly, an oxidative environment favors further oxidation and self-aggregation of proteins in damaged neurons, which promotes neuronal death that subsequently stimulates TLRs and the NLRP3 inflammasome in microglia enhancing the production of IL-1β.
Figure 2 Neuron–microglia crosstalk. An amplification of neuron–microglia interactions is shown in green arrow signals. Homeostatic neurons actively produce anti-inflammatory signals aimed at inhibiting the acquisition of the inflammatory M1-like phenotype by microglial cells. During neurodegenerative disorders or after nervous system injury, cellular mediators associated with damage are activated (salmon arrows) triggering the M1 microglia state that releases reactive species of oxygen and nitrogen (ROS and RNS), glutamate and TNF-α (gray arrows) Importantly, an oxidative environment favors further oxidation and self-aggregation of proteins in damaged neurons, which promotes neuronal death that subsequently stimulates TLRs and the NLRP3 inflammasome in microglia enhancing the production of IL-1β.CC BY · PubMed Central
Figure 3 Neuron–astrocyte crosstalk. These neuron–astrocyte interactions are focused on providing neuronal metabolic support, maintenance of the homeostasis through synaptic cleaning, and synaptic modulation.
Figure 3 Neuron–astrocyte crosstalk. These neuron–astrocyte interactions are focused on providing neuronal metabolic support, maintenance of the homeostasis through synaptic cleaning, and synaptic modulation.CC BY · PubMed Central
Figure 4 Inflammatory response in Alzheimer disease (AD). Amyloid precursor protein (APP) is cleaved producing amyloid-β peptide that aggregates. These aggregates activate microglia cells through TLRs and RAGE changing the transcriptional program of the microglia cells activating the expression of transcription factors like AP-1 and NF-κB, which in turn trigger the production of reactive oxygen species (ROS) and inflammatory cytokines. These cytokines amplify the proinflammatory state by the stimulation of the astrocytes that together act directly on the neuronal population (cholinergic, glutamatergic, and GABAergic neurons) inducing neuronal cell death. Apoptosis of neurons results in release of ATP, which further activates microglia through purinergic P2X7 receptor, entering in an autostimulatory loop inducing T-cell infiltration.
Figure 4 Inflammatory response in Alzheimer disease (AD). Amyloid precursor protein (APP) is cleaved producing amyloid-β peptide that aggregates. These aggregates activate microglia cells through TLRs and RAGE changing the transcriptional program of the microglia cells activating the expression of transcription factors like AP-1 and NF-κB, which in turn trigger the production of reactive oxygen species (ROS) and inflammatory cytokines. These cytokines amplify the proinflammatory state by the stimulation of the astrocytes that together act directly on the neuronal population (cholinergic, glutamatergic, and GABAergic neurons) inducing neuronal cell death. Apoptosis of neurons results in release of ATP, which further activates microglia through purinergic P2X7 receptor, entering in an autostimulatory loop inducing T-cell infiltration.CC BY · PubMed Central
Figure 5 Inflammation in Parkinson disease (PD). The hallmark of this disease is characterized by the presence of intracellular inclusions of α-synuclein aggregates in Lewy bodies. When they are released from neurons, they activate microglia cells through a TLR-independent mechanism. This leads to the activation of NF-κB and production of ROS and proinflammatory cytokines that simultaneously activate the astrocytes and in a combinatorial manner promote neurotoxicity.
Figure 5 Inflammation in Parkinson disease (PD). The hallmark of this disease is characterized by the presence of intracellular inclusions of α-synuclein aggregates in Lewy bodies. When they are released from neurons, they activate microglia cells through a TLR-independent mechanism. This leads to the activation of NF-κB and production of ROS and proinflammatory cytokines that simultaneously activate the astrocytes and in a combinatorial manner promote neurotoxicity.CC BY · PubMed Central
Figure 6 Inflammation in amyotrophic lateral sclerosis (ALS). Toxic aggregates of SOD1, TDP-43, or FUS can induce inflammatory responses and activate microglia via TLR2 and CD14. This leads to the expression of the transcription factor NF-κB and AP1, which trigger the production of proinflammatory cytokines and apoptosis inducers such as TNF-α and FASL. Dying motor neurons (MNs) release ATP, which further activates the purinergic receptor P2X7 expressed in microglia.
Figure 6 Inflammation in amyotrophic lateral sclerosis (ALS). Toxic aggregates of SOD1, TDP-43, or FUS can induce inflammatory responses and activate microglia via TLR2 and CD14. This leads to the expression of the transcription factor NF-κB and AP1, which trigger the production of proinflammatory cytokines and apoptosis inducers such as TNF-α and FASL. Dying motor neurons (MNs) release ATP, which further activates the purinergic receptor P2X7 expressed in microglia.CC BY · PubMed Central

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Metadata

Authors
Bernaus, A., Blanco, S., & Sevilla, A.
Affiliations
  • Universitat de Barcelona (ES)
  • Consejo Superior de Investigaciones Científicas (ES)
Corresponding author
Sevilla, Ana
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2020-07-29
Volume
14
Pages
209-209
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2020.00209
PMC
PMC7403442
OpenAlex
W3046216659
Cited by
157
References
134
Citations by year
2026: 16 · 2025: 20 · 2024: 39 · 2023: 29 · 2022: 32 · 2021: 20 · 2020: 1
FWCI
7.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerio de Ciencia y Tecnología (RYC-2016-19962)
  • Ministerio de Ciencia, Innovación y Universidades (PGC2018-098626-B100)
  • Merck Company Foundation
  • Fundación Científica Asociación Española Contra el Cáncer
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
neuroinflammation, astrocytes, blood-brain barrier, infiltrating T cells, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, immunomodulation, neuron-glia interactions

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