Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage
Open accessAbstract
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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TLR4 knockout and knockdown with siRNAs block alcohol-induced neuroinflammatory responses in vivo.
“TLR4 knockout (Fernandez-Lizarbe et al., 2009) and knockdown with siRNAs (Alfonso-Loeches et al., 2010) also blocked alcohol-induced neuroinflammatory responses in vivo.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Alfonso-Loeches et al., 2010
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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.
- 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
- 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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