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G enetic deletion of x CT attenuates peripheral and central inflammation and mitigates LPS ‐induced sickness and depressive‐like behavior in mice
Author(s) -
Albertini Giulia,
Deneyer Lauren,
OttestadHansen Sigrid,
Zhou Yun,
Ates Gamze,
Walrave Laura,
Demuyser Thomas,
Bentea Eduard,
Sato Hideyo,
De Bundel Dimitri,
Danbolt Niels C.,
Massie Ann,
Smolders Ilse
Publication year - 2018
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23343
Subject(s) - inflammation , microglia , sickness behavior , lipopolysaccharide , central nervous system , immune system , knockout mouse , hippocampal formation , glutamate receptor , immunology , in vivo , biology , pharmacology , medicine , neuroscience , receptor , biochemistry , microbiology and biotechnology
The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive‐like symptoms. In vitro , the response to LPS treatment has been shown to involve enhanced expression of systemx c − . This cystine‐glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS‐injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS‐induced sickness and depressive‐like behavior were significantly attenuated in xCT‐deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of systemx c −in peripheral and central inflammation in vivo and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.