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. SullivanJoaquin M. Espinosa

    Research output: Contribution to journalArticleResearch

    12 Citations (Scopus)

    Abstract

    © 2019, The Author(s). 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.
    Original languageEnglish
    Article number4766
    JournalNature Communications
    Volume10
    DOIs
    Publication statusPublished - 1 Dec 2019

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