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The roles of type I IFNs on distinct myeloid cell subsets during CNS autoimmunity

Subject Area Molecular and Cellular Neurology and Neuropathology
Term from 2008 to 2015
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 106373282
 
Final Report Year 2016

Final Report Abstract

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.

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