Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12739-9
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Funding
- NIH [R01AI150305, R01AI145988, T15LM009451, T32CA190216, UL1TR002535, R01HL137990-02S1, P30 CA046934]
- Linda Crnic Institute for Down Syndrome
- Global Down Syndrome Foundation
- Anna and John J. Sie Foundation
- Boettcher Foundation
- University of Colorado School of Medicine
- Carlos III Institute of Health, Spain [PI14/01126, PI17/01019, PI13/01532, PI16/01825, PI14/1561, PI17/01896, PI18/00335]
- National Institutes of Health (NIA) [1R01AG056850-01A1, R21AG056974, R01AG061566]
- CIBERNED program (Program 1, Alzheimer Disease) - Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, Una manera de hacer Europa
- Marato TV3 grant [20141210, 044412]
- Generalitat de Catalunya [SLT006/17/00119]
- Fundacio Bancaria La Caixa
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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.
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