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

Author:

Powers Rani K.,Culp-Hill Rachel,Ludwig Michael P.,Smith Keith P.,Waugh Katherine A.,Minter Ross,Tuttle Kathryn D.ORCID,Lewis Hannah C.,Rachubinski Angela L.,Granrath Ross E.ORCID,Carmona-Iragui María,Wilkerson Rebecca B.,Kahn Darcy E.,Joshi Molishree,Lleó Alberto,Blesa Rafael,Fortea Juan,D’Alessandro Angelo,Costello James C.,Sullivan Kelly D.ORCID,Espinosa Joaquin M.

Abstract

AbstractTrisomy 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 overexpressIDO1, 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 ofIFNreceptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causingIDO1overexpression 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.

Funder

Ministry of Economy and Competitiveness | Instituto de Salud Carlos III

Fundació la Marató de TV3

Generalitat de Catalunya

Boettcher Foundation

Global Down Syndrome Foundation

Anna and John J. Sie Foundation University of Colorado School of Medicine Linda Crnic Institute for Down Syndrome

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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