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Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance

Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E(2), an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavi...

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Autores principales: Nie, Xiang, Kitaoka, Shiho, Shinohara, Masakazu, Kakizuka, Akira, Narumiya, Shuh, Furuyashiki, Tomoyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879743/
https://www.ncbi.nlm.nih.gov/pubmed/31772309
http://dx.doi.org/10.1038/s41598-019-54082-5
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author Nie, Xiang
Kitaoka, Shiho
Shinohara, Masakazu
Kakizuka, Akira
Narumiya, Shuh
Furuyashiki, Tomoyuki
author_facet Nie, Xiang
Kitaoka, Shiho
Shinohara, Masakazu
Kakizuka, Akira
Narumiya, Shuh
Furuyashiki, Tomoyuki
author_sort Nie, Xiang
collection PubMed
description Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E(2), an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE(2) synthesis in the brain and whether TLR2/4 are involved in the PGE(2) synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE(2) synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE(2) in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE(2) synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE(2) synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE(2) synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.
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spelling pubmed-68797432019-12-05 Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance Nie, Xiang Kitaoka, Shiho Shinohara, Masakazu Kakizuka, Akira Narumiya, Shuh Furuyashiki, Tomoyuki Sci Rep Article Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E(2), an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE(2) synthesis in the brain and whether TLR2/4 are involved in the PGE(2) synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE(2) synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE(2) in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE(2) synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE(2) synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE(2) synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance. Nature Publishing Group UK 2019-11-26 /pmc/articles/PMC6879743/ /pubmed/31772309 http://dx.doi.org/10.1038/s41598-019-54082-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nie, Xiang
Kitaoka, Shiho
Shinohara, Masakazu
Kakizuka, Akira
Narumiya, Shuh
Furuyashiki, Tomoyuki
Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title_full Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title_fullStr Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title_full_unstemmed Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title_short Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance
title_sort roles of toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin e(2) synthesis in the brain and their behavioral relevance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879743/
https://www.ncbi.nlm.nih.gov/pubmed/31772309
http://dx.doi.org/10.1038/s41598-019-54082-5
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