Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling

Chronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll‐like receptor (TLR) activation plays a key role in ethanol‐induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or t...

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Bibliographic Details
Published in:Addiction biology 2018-05, Vol.23 (3), p.889-903
Main Authors: McCarthy, Gizelle M., Warden, Anna S., Bridges, Courtney R., Blednov, Yuri A., Harris, R. Adron
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - drug effects
Adaptor Proteins, Vesicular Transport - genetics
Adaptor Proteins, Vesicular Transport - immunology
Alcohol
Alcohol use
Aminopyridines - pharmacology
Amlexanox
Amygdala
Amygdala - drug effects
Amygdala - immunology
Animals
Brain - drug effects
Brain - immunology
Central Nervous System Depressants - pharmacology
Chemokine CXCL10 - drug effects
Chemokine CXCL10 - immunology
chronic ethanol
CXCL10 protein
Drinking behavior
Ethanol
Ethanol - pharmacology
I-kappa B Kinase - antagonists & inhibitors
Immune response
Interferon
Lipopolysaccharide Receptors - drug effects
Lipopolysaccharide Receptors - immunology
Mice
Mice, Inbred C57BL
mRNA
MyD88 protein
neuroimmune
Neuroimmunomodulation - drug effects
Neuroimmunomodulation - immunology
Nucleus accumbens
Nucleus Accumbens - drug effects
Nucleus Accumbens - immunology
Prefrontal cortex
Prefrontal Cortex - drug effects
Prefrontal Cortex - immunology
Protein Serine-Threonine Kinases - antagonists & inhibitors
RNA, Messenger - drug effects
RNA, Messenger - metabolism
Rodents
Signal Transduction
TLR3 protein
Toll-Like Receptor 2 - drug effects
Toll-Like Receptor 2 - immunology
Toll-Like Receptor 3 - drug effects
Toll-Like Receptor 3 - genetics
Toll-Like Receptor 3 - immunology
Toll-Like Receptor 4 - drug effects
Toll-Like Receptor 4 - immunology
Toll-like receptors
TRIF
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Summary:Chronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll‐like receptor (TLR) activation plays a key role in ethanol‐induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or the TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF) dependent, is activated in response to chronic ethanol. We used voluntary (every‐other‐day) chronic ethanol consumption in adult C57BL/6J mice and measured expression of TLRs and their signaling molecules immediately following consumption and 24 hours after removing alcohol. We focused on the prefrontal cortex where neuroimmune changes are the most robust and also investigated the nucleus accumbens and amygdala. Tlr mRNA and components of the TRIF‐dependent pathway (mRNA and protein) were increased in the prefrontal cortex 24 hours after ethanol and Cxcl10 expression increased 0 hour after ethanol. Expression of Tlr3 and TRIF‐related components increased in the nucleus accumbens, but slightly decreased in the amygdala. In addition, we demonstrate that the IKKε/TBK1 inhibitor Amlexanox decreases immune activation of TRIF‐dependent pathway in the brain and reduces ethanol consumption, suggesting the TRIF‐dependent pathway regulates drinking. Our results support the importance of TLR3 and the TRIF‐dependent pathway in ethanol‐induced neuroimmune signaling and suggest that this pathway could be a target in the treatment of alcohol use disorders. Chronic voluntary alcohol results in time‐dependent changes in toll‐like receptor pathways in the prefrontal cortex. These changes include increased expression of Tlr3, components of the TRIF‐dependent pathway, and the interferon inducible gene Cxcl10. The TRIF‐dependent pathway inhibitor Amlexanox reduces Cxcl10 induction in vivo and decreases ethanol consumption, suggesting a role for the TRIF pathway in the regulation of alcohol consumption.
ISSN:1355-6215
1369-1600
DOI:10.1111/adb.12539