Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

被引：131

作者：

Blank, Thomas ^{[1
]}

Detje, Claudia N. ^{[2
]}

Spiess, Alena ^{[1
]}

Hagemeyer, Nora ^{[1
]}

Brendecke, Stefanie M. ^{[1
]}

Wolfart, Jakob ^{[3
]}

Staszewski, Ori ^{[1
]}

Zoeller, Tanja ^{[1
]}

Papageorgiou, Ismini ^{[4
]}

Schneider, Justus ^{[4
]}

Paricio-Montesinos, Ricardo ^{[1
]}

Eisel, Ulrich L. M. ^{[5
,6
]}

Manahan-Vaughan, Denise ^{[7
]}

Jansen, Stephan ^{[7
]}

Lienenklaus, Stefan ^{[2
,8
]}

Lu, Bao ^{[9
]}

Imai, Yumiko ^{[10
]}

Mueller, Marcus ^{[11
]}

Goelz, Susan E.

Baker, Darren P. ^{[12
]}

Schwaninger, Markus ^{[13
]}

Kann, Oliver ^{[4
]}

Heikenwalder, Mathias ^{[14
,15
]}

Kalinke, Ulrich ^{[2
]}

Prinz, Marco ^{[1
,16
]}

机构：

[1] Univ Freiburg, Inst Neuropathol, Hugstetter Str 55, D-79106 Freiburg, Germany

[2] Ctr Expt & Clin Infect Res, TWINCORE, Inst Expt Infect Res, D-30625 Hannover, Germany

[3] Univ Rostock, Oscar Langendorff Inst Physiol, D-18057 Rostock, Germany

[4] Heidelberg Univ, Inst Physiol & Pathophysiol, D-69120 Heidelberg, Germany

[5] Univ Groningen, Groningen Inst Evolutionary Life Sci, Dept Mol Neurobiol, NL-9700 Groningen, Netherlands

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 Groningen, Netherlands

[7] Ruhr Univ Bochum, Fac Med, Dept Neurophysiol, D-44780 Bochum, Germany

[8] Hannover Med Sch, Inst Lab Anim Sci, Carl Neuberg Str 1, D-30625 Hannover, Germany

[9] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA

[10] Akita Univ, Grad Sch Med, Dept Biol Informat & Expt Therapeut, Akita 0108543, Japan

[11] Univ Klinikum Bonn, Dept Neurol, D-53105 Bonn, Germany

[12] Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA

[13] Med Univ Lubeck, Inst Expt & Clin Pharmacol & Toxicol, D-23538 Lubeck, Germany

[14] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81756 Munich, Germany

[15] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany

[16] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany

来源：

IMMUNITY | 2016年 / 44卷 / 04期

关键词：

CENTRAL-NERVOUS-SYSTEM; DOUBLE-STRANDED-RNA; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; MAJOR DEPRESSION; IN-VIVO; RIG-I; MICE; CELLS; INFLAMMATION;

D O I：

10.1016/j.immuni.2016.04.005

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

引用

页码：901 / 912

页数：12

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