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

Autor: Hideyo Sato, Laura Walrave, Yun Zhou, Ilse Julia Smolders, Sigrid Ottestad-Hansen, Lauren Deneyer, Ann Massie, Thomas Demuyser, Eduard Bentea, Dimitri De Bundel, Niels C. Danbolt, Giulia Albertini, Gamze Ates
Přispěvatelé: Faculty of Medicine and Pharmacy, Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology
Rok vydání: 2018
Předmět:
0301 basic medicine
Lipopolysaccharides
Male
Lipopolysaccharide
medicine.medical_treatment
RNA
Messenger/metabolism
Astrocytes/metabolism
Hippocampus
chemistry.chemical_compound
0302 clinical medicine
Illness Behavior/physiology
Sickness behavior
Amino Acid Transport System y+/deficiency
Illness Behavior
Mice
Knockout
Microglia
Depression
Inflammation/metabolism
Cytokines/metabolism
Glial Fibrillary Acidic Protein/metabolism
medicine.anatomical_structure
Cytokine
Excitatory Amino Acid Transporter 2
Cytokines
medicine.symptom
medicine.medical_specialty
Depression/metabolism
Amino Acid Transport System y+
Excitatory Amino Acid Transporter 2/metabolism
Central nervous system
Hippocampus/metabolism
Inflammation
Biology
Microglia/metabolism
03 medical and health sciences
Cellular and Molecular Neuroscience
Immune system
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Animals
RNA
Messenger
neurology
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
chemistry
Astrocytes
System X
030217 neurology & neurosurgery
Gene Deletion
Zdroj: Glia. 66(9)
ISSN: 1098-1136
Popis: 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 x 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 system x 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.
Databáze: OpenAIRE
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