Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

Rani K. Powers, Rachel Culp-Hill, Michael P. Ludwig, Keith P. Smith, Katherine A. Waugh, Ross Minter, Kathryn D. Tuttle, Hannah C. Lewis, Angela L. Rachubinski, Ross E. Granrath, María Carmona-Iragui, Rebecca B. Wilkerson, Darcy E. Kahn, Molishree Joshi, Alberto Lleó, Rafael Blesa, Juan Fortea, Angelo D’Alessandro, James C. Costello, Kelly D. Sullivan () and Joaquin M. Espinosa ()
Additional contact information
Rani K. Powers: University of Colorado Anschutz Medical Campus
Rachel Culp-Hill: University of Colorado Anschutz Medical Campus
Michael P. Ludwig: University of Colorado Anschutz Medical Campus
Keith P. Smith: University of Colorado Anschutz Medical Campus
Katherine A. Waugh: University of Colorado Anschutz Medical Campus
Ross Minter: University of Colorado Anschutz Medical Campus
Kathryn D. Tuttle: University of Colorado Anschutz Medical Campus
Hannah C. Lewis: University of Colorado Anschutz Medical Campus
Angela L. Rachubinski: University of Colorado Anschutz Medical Campus
Ross E. Granrath: University of Colorado Anschutz Medical Campus
María Carmona-Iragui: Universitat Autonoma de Barcelona, CIBERNED
Rebecca B. Wilkerson: University of Colorado Anschutz Medical Campus
Darcy E. Kahn: University of Colorado Anschutz Medical Campus
Molishree Joshi: University of Colorado Anschutz Medical Campus
Alberto Lleó: Universitat Autonoma de Barcelona, CIBERNED
Rafael Blesa: Universitat Autonoma de Barcelona, CIBERNED
Juan Fortea: Universitat Autonoma de Barcelona, CIBERNED
Angelo D’Alessandro: University of Colorado Anschutz Medical Campus
James C. Costello: University of Colorado Anschutz Medical Campus
Kelly D. Sullivan: University of Colorado Anschutz Medical Campus
Joaquin M. Espinosa: University of Colorado Anschutz Medical Campus

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. 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, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

Date: 2019
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DOI: 10.1038/s41467-019-12739-9

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