Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 67, Issue -, Pages 54-58Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2017.08.020
Keywords
Aversion; Interferon; Chemokines; Endothelium; Lipopolysaccharide; Behavior; Sickness; Depression
Categories
Funding
- European Research Council
- Swedish Medical Research Council
- Knut and Alice Wallenberg foundation
- Swedish Brain foundation
- Parkinsonstiftelsen
- Region Ostergotland
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Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-gamma (IFN-gamma) in the aversive response to systemic inflammation induced by a low dose (10 p.g/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-gamma expression in the blood and deletion of IFN-y or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-y receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation induced aversion was blocked in mice lacking Cxc110 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-y receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-gamma action. Collectively, these findings show that circulating IFN-y that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-inducedaversion. (C) 2017 Elsevier Inc. All rights reserved.
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