Cargando…
System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness
Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x(c)(−) plays a role i...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525204/ https://www.ncbi.nlm.nih.gov/pubmed/31101857 http://dx.doi.org/10.1038/s41598-019-44006-8 |
_version_ | 1783419677610868736 |
---|---|
author | Kitagawa, Yoshinori Nakaso, Kazuhiro Horikoshi, Yosuke Morimoto, Masaki Omotani, Takuma Otsuki, Akihiro Inagaki, Yoshimi Sato, Hideyo Matsura, Tatsuya |
author_facet | Kitagawa, Yoshinori Nakaso, Kazuhiro Horikoshi, Yosuke Morimoto, Masaki Omotani, Takuma Otsuki, Akihiro Inagaki, Yoshimi Sato, Hideyo Matsura, Tatsuya |
author_sort | Kitagawa, Yoshinori |
collection | PubMed |
description | Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x(c)(−) plays a role in PSNPI. We established a mouse model of PSNPI by lipopolysaccharide (LPS) treatment that shows a disturbance of short/working memory and depression-like hypoactivity. Glutamate receptor antagonists (MK801 and DNQX) reduced these phenotypes, and isolated microglia from LPS-treated mice released abundant glutamate. We identified system x(c)(−) as a source of the extracellular glutamate. xCT, a component of system x(c)(−), was induced and expressed in microglia after LPS treatment. In xCT knockout mice, PSNPI were decreased compared to those in wildtype mice. Moreover, TNF-α and IL-1β expression in wildtype mice was increased after LPS treatment, but inhibited in xCT knockout mice. Thus, system x(c)(−) in microglia may be a therapeutic target for PSNPI. The administration of sulfasalazine, an inhibitor of xCT, in symptomatic and post-symptomatic mice improved PSNPI. Our results suggest that glutamate released from microglia through system x(c)(−) plays a critical role in the manifestations of PSNPI and that system x(c)(−) may be a therapeutic target for PSNPI. |
format | Online Article Text |
id | pubmed-6525204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-65252042019-05-29 System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness Kitagawa, Yoshinori Nakaso, Kazuhiro Horikoshi, Yosuke Morimoto, Masaki Omotani, Takuma Otsuki, Akihiro Inagaki, Yoshimi Sato, Hideyo Matsura, Tatsuya Sci Rep Article Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x(c)(−) plays a role in PSNPI. We established a mouse model of PSNPI by lipopolysaccharide (LPS) treatment that shows a disturbance of short/working memory and depression-like hypoactivity. Glutamate receptor antagonists (MK801 and DNQX) reduced these phenotypes, and isolated microglia from LPS-treated mice released abundant glutamate. We identified system x(c)(−) as a source of the extracellular glutamate. xCT, a component of system x(c)(−), was induced and expressed in microglia after LPS treatment. In xCT knockout mice, PSNPI were decreased compared to those in wildtype mice. Moreover, TNF-α and IL-1β expression in wildtype mice was increased after LPS treatment, but inhibited in xCT knockout mice. Thus, system x(c)(−) in microglia may be a therapeutic target for PSNPI. The administration of sulfasalazine, an inhibitor of xCT, in symptomatic and post-symptomatic mice improved PSNPI. Our results suggest that glutamate released from microglia through system x(c)(−) plays a critical role in the manifestations of PSNPI and that system x(c)(−) may be a therapeutic target for PSNPI. Nature Publishing Group UK 2019-05-17 /pmc/articles/PMC6525204/ /pubmed/31101857 http://dx.doi.org/10.1038/s41598-019-44006-8 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 Kitagawa, Yoshinori Nakaso, Kazuhiro Horikoshi, Yosuke Morimoto, Masaki Omotani, Takuma Otsuki, Akihiro Inagaki, Yoshimi Sato, Hideyo Matsura, Tatsuya System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title | System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title_full | System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title_fullStr | System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title_full_unstemmed | System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title_short | System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
title_sort | system x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525204/ https://www.ncbi.nlm.nih.gov/pubmed/31101857 http://dx.doi.org/10.1038/s41598-019-44006-8 |
work_keys_str_mv | AT kitagawayoshinori systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT nakasokazuhiro systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT horikoshiyosuke systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT morimotomasaki systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT omotanitakuma systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT otsukiakihiro systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT inagakiyoshimi systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT satohideyo systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness AT matsuratatsuya systemxcinmicrogliaisanoveltherapeutictargetforpostsepticneurologicalandpsychiatricillness |