Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice

Giulia Albertini, Lauren Deneyer, Sigrid Ottestad-Hansen, Yun Zhou, Gamze Ates, Laura Walrave, Thomas Demuyser, Eduard Bentea, Hideyo Sato, Dimitri De Bundel, Niels C Danbolt, Ann Massie, Ilse Smolders

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25 Citations (Scopus)
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Abstract

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 system <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msubsup><mml:mrow><mml:mi>x</mml:mi></mml:mrow> <mml:mrow><mml:mi>c</mml:mi></mml:mrow> <mml:mrow><mml:mo>-</mml:mo></mml:mrow> </mml:msubsup> </mml:math> . 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 system <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msubsup><mml:mrow><mml:mi>x</mml:mi></mml:mrow> <mml:mrow><mml:mi>c</mml:mi></mml:mrow> <mml:mrow><mml:mo>-</mml:mo></mml:mrow> </mml:msubsup> </mml:math> 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.

Original languageEnglish
Pages (from-to)1845-1861
Number of pages17
JournalGlia
Volume66
Issue number9
DOIs
Publication statusPublished - Sep 2018

Bibliographical note

© 2018 Wiley Periodicals, Inc.

Keywords

  • Amino Acid Transport System y+/deficiency
  • Animals
  • Astrocytes/metabolism
  • Cytokines/metabolism
  • Depression/metabolism
  • Excitatory Amino Acid Transporter 2/metabolism
  • Gene Deletion
  • Glial Fibrillary Acidic Protein/metabolism
  • Hippocampus/metabolism
  • Illness Behavior/physiology
  • Inflammation/metabolism
  • Lipopolysaccharides
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia/metabolism
  • RNA, Messenger/metabolism

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