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 xc-. ⋯ 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 xc- 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.
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, and Ilse Smolders.
Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, 1090, Belgium.