Cited by 579Neuroinflammation and Neurodegeneration MechanismsAlcohol Consumption and Health EffectsImmune Response and Inflammation

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Pivotal Role of TLR4 Receptors in Alcohol-Induced Neuroinflammation and Brain Damage

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Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A. M., Sanchez-Vera, I., Guerri, C.·2010·Journal of Neuroscience

DOI 10.1523/jneurosci.0976-10.2010PMC PMC6634595

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Abstract

Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation. This study aims to establish the potential role of TLR4 in both ethanol-induced glial activation and brain damage. Here we report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells since the knockdown of TLR4, by using both small interfering RNA or cells from TLR4-deficient mice, abolished the activation of microtubule-associated protein kinase and nuclear factor-kappaB pathways and the production of inflammatory mediators by astrocytes. Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b (microglial marker) and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels [interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6] in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.

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Authors: Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A. M., Sanchez-Vera, I., & Guerri, C.
Affiliations: Centro de Investigacion Principe Felipe (ES)
Corresponding author: Guerri, C.
ORCID: Blanco, A. M.
Guerri, C.
Venue: Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2010-06-16
Volume: 30
Issue: 24
Pages: 8285-8295
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.0976-10.2010
PMC: PMC6634595
OpenAlex: W1975931952
Cited by: 579
References: 66
Citations by year: 2026: 17 · 2025: 35 · 2024: 41 · 2023: 39 · 2022: 41 · 2021: 46 · 2020: 44 · 2019: 41 · 2018: 30 · 2017: 56 · 2016: 46 · 2015: 24 · 2014: 36 · 2013: 23 · 2012: 35
FWCI: 16.09
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Ministerio de Ciencia e Innovación
Plan Nacional sobre Drogas
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: TLR4, ethanol, glial activation, astrocytes, microglia, neurodegeneration, brain injury, MAPK signaling, NF-κB signaling, inflammatory mediators, apoptosis, caspase-3, inducible nitric oxide synthase, cyclooxygenase-2, cytokines, female mice, cerebral cortex
MeSH terms: Ethanol, Animals, Astrocytes, Brain Injuries, Calcium-Binding Proteins, Central Nervous System Depressants, Disease Models, Animal, Encephalitis, Female, Gene Expression Regulation, Lipopolysaccharides, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, RNA, Messenger, Time Factors, Tumor Necrosis Factor-alpha, Rats, Wistar, Mice, Knockout, Statistics, Nonparametric, Lipopolysaccharide Receptors, RNA, Small Interfering, Green Fluorescent Proteins, Toll-Like Receptor 4, Lymphocyte Antigen 96, Mice, Rats, Cyclooxygenase 2, Caspase 3, Interleukin-1beta

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Pivotal Role of TLR4 Receptors in Alcohol-Induced Neuroinflammation and Brain Damage

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