PT  - JOURNAL ARTICLE
AU  - Rani K. Powers
AU  - Kelly D. Sullivan
AU  - Rachel Culp-Hill
AU  - Michael P. Ludwig
AU  - Keith P. Smith
AU  - Katherine A. Waugh
AU  - Ross Minter
AU  - Kathryn D. Tuttle
AU  - Hannah C. Lewis
AU  - Angela L. Rachubinski
AU  - Ross E. Granrath
AU  - Rebecca B. Wilkerson
AU  - Darcy E. Kahn
AU  - Molishree Joshi
AU  - Angelo D’Alessandro
AU  - James C. Costello
AU  - Joaquin M. Espinosa
TI  - Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
AID  - 10.1101/403642
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 403642
4099  - http://biorxiv.org/content/early/2019/01/11/403642.short
4100  - http://biorxiv.org/content/early/2019/01/11/403642.full
AB  - Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here the results of a large metabolomics study showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We found that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we found a positive correlation between levels of specific inflammatory cytokines and KP dysregulation. Using metabolic flux assays, we found that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, KP dysregulation is conserved in a mouse model of DS carrying triplication of the IFN receptors. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.