CoChat
Sign Up
Cited by 250Neuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury Research

The DOI matches its Crossref record; 188 of the 188 references it cites were found in a registry or an index.

Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration

Open access
Shao, Fangjie, Wang, Xiaoyu, Wu, Haijian, Wu, Qun, Zhang, Jianmin·2022·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2022.825086PMC PMC8990307
Open this paper in CoChat — free accountOpen PDF

Abstract

Traumatic brain injury (TBI) is one of the most common diseases in the central nervous system (CNS) with high mortality and morbidity. Patients with TBI usually suffer many sequelae in the life time post injury, including neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the pathological mechanisms connecting these two processes have not yet been fully elucidated. It is important to further investigate the pathophysiological mechanisms underlying TBI and TBI-induced neurodegeneration, which will promote the development of precise treatment target for these notorious neurodegenerative consequences after TBI. A growing body of evidence shows that neuroinflammation is a pivotal pathological process underlying chronic neurodegeneration following TBI. Microglia, as the immune cells in the CNS, play crucial roles in neuroinflammation and many other CNS diseases. Of interest, microglial activation and functional alteration has been proposed as key mediators in the evolution of chronic neurodegenerative pathology following TBI. Here, we review the updated studies involving phenotypical and functional alterations of microglia in neurodegeneration after injury, survey key molecules regulating the activities and functional responses of microglia in TBI pathology, and explore their potential implications to chronic neurodegeneration after injury. The work will give us a comprehensive understanding of mechanisms driving TBI-related neurodegeneration and offer novel ideas of developing corresponding prevention and treatment strategies for this disease.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnagi.2022.825086

Cites

188 of 188 references verified0 citation errors · 0 not checkable

Statistics

Figures

FIGURE 1 Heterogeneity of microglia: phenotypic and functional diversity. In response to disturbance of brain homeostasis like injury or disease, microglia can become polarized toward M1-like and M2-like activation states that can have distinct roles in neurodegeneration and tissue repair. An environment rich with the classical pro-inflammatory stimuli, such as IFN-γ and LPS, promotes the polarization of resting microglia into an M1 phenotype. M1-like microglia are characterized by upregulated expression of phenotypic protein markers such as IL-1β, TNFα, IL-6, and iNOS. They release pro-inflammatory cytokines, chemokines and free radicals that impair brain repair and contribute to chronic neuroinflammation, oxidative stress and long-term neurological impairments. In contrast, a neuroinflammatory environment rich in anti-inflammatory IL-4 or IL-13 drives the development of an M2 phenotype. M2-like microglia upregulate protein markers such as CD206, CD163, FCγR, arginase 1, Ym-1, and TGFβ. M2-like microglia release anti- inflammatory cytokines, neurotrophic factors and proteases, and they have increased phagocytic activity. M2-like microglia promote immunosuppression and resolution of M1-mediated neuroinflammation, and participate in CNS remodeling and repair by modulating neurorestorative processes such as neurogenesis, angiogenesis, oligodendrogenesis and remyelination.
FIGURE 1 Heterogeneity of microglia: phenotypic and functional diversity. In response to disturbance of brain homeostasis like injury or disease, microglia can become polarized toward M1-like and M2-like activation states that can have distinct roles in neurodegeneration and tissue repair. An environment rich with the classical pro-inflammatory stimuli, such as IFN-γ and LPS, promotes the polarization of resting microglia into an M1 phenotype. M1-like microglia are characterized by upregulated expression of phenotypic protein markers such as IL-1β, TNFα, IL-6, and iNOS. They release pro-inflammatory cytokines, chemokines and free radicals that impair brain repair and contribute to chronic neuroinflammation, oxidative stress and long-term neurological impairments. In contrast, a neuroinflammatory environment rich in anti-inflammatory IL-4 or IL-13 drives the development of an M2 phenotype. M2-like microglia upregulate protein markers such as CD206, CD163, FCγR, arginase 1, Ym-1, and TGFβ. M2-like microglia release anti- inflammatory cytokines, neurotrophic factors and proteases, and they have increased phagocytic activity. M2-like microglia promote immunosuppression and resolution of M1-mediated neuroinflammation, and participate in CNS remodeling and repair by modulating neurorestorative processes such as neurogenesis, angiogenesis, oligodendrogenesis and remyelination.CC BY · PubMed Central
FIGURE 2 Schematic diagram of microglia-mediated neuroinflammation signaling pathways after TBI. In response to TBI, DAMPs such as HMGB1 can promote priming of the NLRP3 inflammasome through NF-κB signaling. In microglia, activation of P2X7 receptor could stimulate the NLRP3 inflammasome, which subsequently leads to the outflow of pro-inflammatory cytokines including IL-18 and IL-1β. CX3CL1 is also known to induce microglia activation through intracellular phosphorylation of microglial p38 MAPK. Further, treatment of cultured microglia with CX3CL1 promoted cell survival and inhibited Fas ligand-induced cell death via the Akt signaling pathway. TLR signaling initiates acute inflammatory response by promoting the release of pro-inflammatory cytokines. Ligand binding to TLR4 activates either a MyD88-dependent NF-κB activation or MyD88-independent activation of interferon regulatory factor-3 (IRF-3) activation and the subsequent expression of IFNβ. The TREM2 pathway is responsible for switching from a homeostatic to a neurodegenerative microglial phenotype after phagocytosis of apoptotic neurons. Upon activation, the PPARs regulate inflammation via trans-reexpression of multiple inflammatory signaling systems such as NFκB, activator protein-1 (AP-1), signal transducer and activator of transcription (STAT) to result in M1/M2 microglia polarization and facilitate it toward an anti-inflammatory state. In LPS induced neuroinflammation, LRRK2 could phosphorylate p53 and promote the production of pro-inflammatory cytokine such as tumor necrosis factor (TNF)-α. Activation of NOX2 aggravated inflammatory-mediated neurodegeneration after TBI via inhibiting switch from M1-like activation to M2- like activation of microglia. Pro-inflammatory cytokines expressed by microglia, including interferon-γ, interleukin-1β, and tumor necrosis factor-α, can specifically stimulate Aβ accumulation while anti-inflammatory cytokines such as IL-1ra, IL-10, and TGF preclude formation of Aβ. HMGB1, high mobility group box 1; N-FκB, nuclear factor-kappa B; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; IFN-β, IRF-3-inducing interferon-b. TREM2, triggering receptor expressed on myeloid cells 2. LRRK2, leucine-rich repeat kinase 2; LPS, lipopolysaccharide; PPARγ, peroxisome proliferator-activated receptor gamma. IL-1ra, interleukin-1 receptor antagonist; Aβ, beta amyloid.
FIGURE 2 Schematic diagram of microglia-mediated neuroinflammation signaling pathways after TBI. In response to TBI, DAMPs such as HMGB1 can promote priming of the NLRP3 inflammasome through NF-κB signaling. In microglia, activation of P2X7 receptor could stimulate the NLRP3 inflammasome, which subsequently leads to the outflow of pro-inflammatory cytokines including IL-18 and IL-1β. CX3CL1 is also known to induce microglia activation through intracellular phosphorylation of microglial p38 MAPK. Further, treatment of cultured microglia with CX3CL1 promoted cell survival and inhibited Fas ligand-induced cell death via the Akt signaling pathway. TLR signaling initiates acute inflammatory response by promoting the release of pro-inflammatory cytokines. Ligand binding to TLR4 activates either a MyD88-dependent NF-κB activation or MyD88-independent activation of interferon regulatory factor-3 (IRF-3) activation and the subsequent expression of IFNβ. The TREM2 pathway is responsible for switching from a homeostatic to a neurodegenerative microglial phenotype after phagocytosis of apoptotic neurons. Upon activation, the PPARs regulate inflammation via trans-reexpression of multiple inflammatory signaling systems such as NFκB, activator protein-1 (AP-1), signal transducer and activator of transcription (STAT) to result in M1/M2 microglia polarization and facilitate it toward an anti-inflammatory state. In LPS induced neuroinflammation, LRRK2 could phosphorylate p53 and promote the production of pro-inflammatory cytokine such as tumor necrosis factor (TNF)-α. Activation of NOX2 aggravated inflammatory-mediated neurodegeneration after TBI via inhibiting switch from M1-like activation to M2- like activation of microglia. Pro-inflammatory cytokines expressed by microglia, including interferon-γ, interleukin-1β, and tumor necrosis factor-α, can specifically stimulate Aβ accumulation while anti-inflammatory cytokines such as IL-1ra, IL-10, and TGF preclude formation of Aβ. HMGB1, high mobility group box 1; N-FκB, nuclear factor-kappa B; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; IFN-β, IRF-3-inducing interferon-b. TREM2, triggering receptor expressed on myeloid cells 2. LRRK2, leucine-rich repeat kinase 2; LPS, lipopolysaccharide; PPARγ, peroxisome proliferator-activated receptor gamma. IL-1ra, interleukin-1 receptor antagonist; Aβ, beta amyloid.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 188 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Shao, F., Wang, X., Wu, H., Wu, Q., & Zhang, J.
Affiliations
  • First Affiliated Hospital Zhejiang University (CN)
  • Second Affiliated Hospital of Zhejiang University (CN)
Corresponding author
  • Wu, Qun
  • Zhang, Jianmin
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2022-03-25
Volume
14
Pages
825086-825086
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2022.825086
PMC
PMC8990307
OpenAlex
W4220730682
Cited by
250
References
188
Citations by year
2026: 47 · 2025: 85 · 2024: 75 · 2023: 31 · 2022: 11
FWCI
5.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
Keywords
traumatic brain injury, microglia, neuroinflammation, neurodegeneration, microglial activation, Alzheimer's disease, Parkinson's disease, chronic neurodegeneration, microglial phenotype, treatment options

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review