The roles of type I IFNs on distinct myeloid cell subsets during CNS autoimmunity
Zusammenfassung der Projektergebnisse
Sickness behavior and cognitive dysfunction occur frequently after application of type I interferons (IFNs) for the treatment of malignancies or in autoimmune disorders by unknown mechanisms. Here we show that during sickness behavior, ssRNA viruses, dsRNA ligands, and IFNs share molecular pathways that involve engagement of MDA5, RIG-I, and IPS-1, subsequently inducing an IFN signature specifically in brain endothelia of mice. Mice with conditional myeloid or neuroectodermal IFN receptor chain 1 (IFNAR) deletion were not protected from behavioral alterations whereas IFNAR on brain endothelia was indispensable. By using gene profiling we identified that endothelial-derived CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identify brain endothelial cells as natural gate keepers for virusinduced sickness behavior, demonstrate tissue specific IFNAR engagement, and establish the CXCL10/CXCR3 axis as a potential target for the treatment of cognitive and behavioral changes during virus infection and type I IFN therapy.
Projektbezogene Publikationen (Auswahl)
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Brain endothelial and epithelial IFNAR is key for virus-induced sickness behavior and cognitive impairment. Immunity, 2016, 44(4):901-12
Blank T, Detje CN, Spieß A, Hagemeyer N, Brendecke SM, Wolfart J, Staszewski O, Zöller T, Papageorgiou I, Schneider J, Paricio-Montesinoss R, Eisel ULM, Manahan- Vaughan D, Jansen S, Lienenklaus S, Lu B, Imai Y, Müller M, Goelz SE. Baker DP, Schwaninger M, Kann O, Heikenwalder M, Kalinke U, Prinz M
