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

Author

Listed:
  • Rani K. Powers

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Rachel Culp-Hill

    (University of Colorado Anschutz Medical Campus)

  • Michael P. Ludwig

    (University of Colorado Anschutz Medical Campus
    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
    University of Colorado Anschutz Medical Campus)

  • Ross E. Granrath

    (University of Colorado Anschutz Medical Campus)

  • María Carmona-Iragui

    (Universitat Autonoma de Barcelona, CIBERNED
    Catalan Down Syndrome Foundation)

  • 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
    Catalan Down Syndrome Foundation)

  • Angelo D’Alessandro

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • James C. Costello

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Kelly D. Sullivan

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Joaquin M. Espinosa

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus
    University of Colorado Boulder)

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.

Suggested Citation

  • 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 Carmo, 2019. "Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12739-9
    DOI: 10.1038/s41467-019-12739-9
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