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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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| Published in: | Addiction biology 2018-05, Vol.23 (3), p.889-903 |
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| creator | McCarthy, Gizelle M. Warden, Anna S. Bridges, Courtney R. Blednov, Yuri A. Harris, R. Adron |
| description | 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. |
| doi_str_mv | 10.1111/adb.12539 |
| format | article |
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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.</description><identifier>ISSN: 1355-6215</identifier><identifier>EISSN: 1369-1600</identifier><identifier>DOI: 10.1111/adb.12539</identifier><identifier>PMID: 28840972</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>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</subject><ispartof>Addiction biology, 2018-05, Vol.23 (3), p.889-903</ispartof><rights>2017 Society for the Study of Addiction</rights><rights>2017 Society for the Study of Addiction.</rights><rights>2018 Society for the Study of Addiction</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5099-f311f11dcd63d1ce82b3331674d8c9814a166a0b660f4b58ce929bbb18bf54313</citedby><cites>FETCH-LOGICAL-c5099-f311f11dcd63d1ce82b3331674d8c9814a166a0b660f4b58ce929bbb18bf54313</cites><orcidid>0000-0001-8579-3027 ; 0000-0001-8870-5950 ; 0000-0003-0607-8469</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fadb.12539$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fadb.12539$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,786,790,891,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28840972$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCarthy, Gizelle M.</creatorcontrib><creatorcontrib>Warden, Anna S.</creatorcontrib><creatorcontrib>Bridges, Courtney R.</creatorcontrib><creatorcontrib>Blednov, Yuri A.</creatorcontrib><creatorcontrib>Harris, R. Adron</creatorcontrib><title>Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling</title><title>Addiction biology</title><addtitle>Addict Biol</addtitle><description>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.</description><subject>Adaptor Proteins, Vesicular Transport - drug effects</subject><subject>Adaptor Proteins, Vesicular Transport - genetics</subject><subject>Adaptor Proteins, Vesicular Transport - immunology</subject><subject>Alcohol</subject><subject>Alcohol use</subject><subject>Aminopyridines - pharmacology</subject><subject>Amlexanox</subject><subject>Amygdala</subject><subject>Amygdala - drug effects</subject><subject>Amygdala - immunology</subject><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Brain - immunology</subject><subject>Central Nervous System Depressants - pharmacology</subject><subject>Chemokine CXCL10 - drug effects</subject><subject>Chemokine CXCL10 - immunology</subject><subject>chronic ethanol</subject><subject>CXCL10 protein</subject><subject>Drinking behavior</subject><subject>Ethanol</subject><subject>Ethanol - pharmacology</subject><subject>I-kappa B Kinase - antagonists & inhibitors</subject><subject>Immune response</subject><subject>Interferon</subject><subject>Lipopolysaccharide Receptors - drug effects</subject><subject>Lipopolysaccharide Receptors - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>mRNA</subject><subject>MyD88 protein</subject><subject>neuroimmune</subject><subject>Neuroimmunomodulation - drug effects</subject><subject>Neuroimmunomodulation - immunology</subject><subject>Nucleus accumbens</subject><subject>Nucleus Accumbens - drug effects</subject><subject>Nucleus Accumbens - immunology</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - drug effects</subject><subject>Prefrontal Cortex - immunology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>RNA, Messenger - drug effects</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>TLR3 protein</subject><subject>Toll-Like Receptor 2 - drug effects</subject><subject>Toll-Like Receptor 2 - immunology</subject><subject>Toll-Like Receptor 3 - drug effects</subject><subject>Toll-Like Receptor 3 - genetics</subject><subject>Toll-Like Receptor 3 - immunology</subject><subject>Toll-Like Receptor 4 - drug effects</subject><subject>Toll-Like Receptor 4 - immunology</subject><subject>Toll-like receptors</subject><subject>TRIF</subject><issn>1355-6215</issn><issn>1369-1600</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kdFKHDEUhkNpqVZ70RcoA72pF-PmJJNM0gvBrlqFBUHW65BkMruR2WSb7LR45yP0Gfskja6KLTQ3J3A-Pv7kR-gD4EMoZ6I7cwiEUfkK7QLlsgaO8ev7O2M1J8B20LucbzAG0jL6Fu0QIRosW7KLTqbLFIO3ldssdYhDZWPI42q98TF8qVIcXBX7aj67opP51cXZ77tfnVu70LmwqbJfBD34sNhHb3o9ZPf-ce6h67PT-fS8nl1-u5gez2rLsJR1TwF6gM52nHZgnSCGUgq8bTphpYBGA-caG85x3xgmrJNEGmNAmJ41FOgeOtp616NZuc6WEEkPap38SqdbFbVXf2-CX6pF_KGYIKJtZRF8fhSk-H10eaNWPls3DDq4OGYFkhLRNIK2Bf30D3oTx1TemxXBpHxqA0AKdbClbIo5J9c_hwGs7rtRpRv10E1hP75M_0w-lVGAyRb46Qd3-3-TOj75ulX-AbOymCc</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>McCarthy, Gizelle M.</creator><creator>Warden, Anna S.</creator><creator>Bridges, Courtney R.</creator><creator>Blednov, Yuri A.</creator><creator>Harris, R. Adron</creator><general>John Wiley & Sons, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8579-3027</orcidid><orcidid>https://orcid.org/0000-0001-8870-5950</orcidid><orcidid>https://orcid.org/0000-0003-0607-8469</orcidid></search><sort><creationdate>201805</creationdate><title>Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling</title><author>McCarthy, Gizelle M. ; Warden, Anna S. ; Bridges, Courtney R. ; Blednov, Yuri A. ; Harris, R. Adron</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5099-f311f11dcd63d1ce82b3331674d8c9814a166a0b660f4b58ce929bbb18bf54313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adaptor Proteins, Vesicular Transport - drug effects</topic><topic>Adaptor Proteins, Vesicular Transport - genetics</topic><topic>Adaptor Proteins, Vesicular Transport - immunology</topic><topic>Alcohol</topic><topic>Alcohol use</topic><topic>Aminopyridines - pharmacology</topic><topic>Amlexanox</topic><topic>Amygdala</topic><topic>Amygdala - drug effects</topic><topic>Amygdala - immunology</topic><topic>Animals</topic><topic>Brain - drug effects</topic><topic>Brain - immunology</topic><topic>Central Nervous System Depressants - pharmacology</topic><topic>Chemokine CXCL10 - drug effects</topic><topic>Chemokine CXCL10 - immunology</topic><topic>chronic ethanol</topic><topic>CXCL10 protein</topic><topic>Drinking behavior</topic><topic>Ethanol</topic><topic>Ethanol - pharmacology</topic><topic>I-kappa B Kinase - antagonists & inhibitors</topic><topic>Immune response</topic><topic>Interferon</topic><topic>Lipopolysaccharide Receptors - drug effects</topic><topic>Lipopolysaccharide Receptors - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>mRNA</topic><topic>MyD88 protein</topic><topic>neuroimmune</topic><topic>Neuroimmunomodulation - drug effects</topic><topic>Neuroimmunomodulation - immunology</topic><topic>Nucleus accumbens</topic><topic>Nucleus Accumbens - drug effects</topic><topic>Nucleus Accumbens - immunology</topic><topic>Prefrontal cortex</topic><topic>Prefrontal Cortex - drug effects</topic><topic>Prefrontal Cortex - immunology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>RNA, Messenger - drug effects</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>TLR3 protein</topic><topic>Toll-Like Receptor 2 - drug effects</topic><topic>Toll-Like Receptor 2 - immunology</topic><topic>Toll-Like Receptor 3 - drug effects</topic><topic>Toll-Like Receptor 3 - genetics</topic><topic>Toll-Like Receptor 3 - immunology</topic><topic>Toll-Like Receptor 4 - drug effects</topic><topic>Toll-Like Receptor 4 - immunology</topic><topic>Toll-like receptors</topic><topic>TRIF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCarthy, Gizelle M.</creatorcontrib><creatorcontrib>Warden, Anna S.</creatorcontrib><creatorcontrib>Bridges, Courtney R.</creatorcontrib><creatorcontrib>Blednov, Yuri A.</creatorcontrib><creatorcontrib>Harris, R. Adron</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Addiction biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCarthy, Gizelle M.</au><au>Warden, Anna S.</au><au>Bridges, Courtney R.</au><au>Blednov, Yuri A.</au><au>Harris, R. Adron</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling</atitle><jtitle>Addiction biology</jtitle><addtitle>Addict Biol</addtitle><date>2018-05</date><risdate>2018</risdate><volume>23</volume><issue>3</issue><spage>889</spage><epage>903</epage><pages>889-903</pages><issn>1355-6215</issn><eissn>1369-1600</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>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.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>28840972</pmid><doi>10.1111/adb.12539</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-8579-3027</orcidid><orcidid>https://orcid.org/0000-0001-8870-5950</orcidid><orcidid>https://orcid.org/0000-0003-0607-8469</orcidid><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling |
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