Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Powers, R. K. (Department of Pharmacology. University of Colorado Anschutz Medical Campus)
Culp-Hill, R. (Department of Biochemistry and Molecular Genetics. University of Colorado Anschutz Medical Campus)
Ludwig, M. P. (Department of Pharmacology. University of Colorado Anschutz Medical Campus)
Smith, K. P. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Waugh, K. A. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Minter, R. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Tuttle, K. D. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Lewis, H. C. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Rachubinski, A. L. (Department of Pediatrics. University of Colorado Anschutz Medical Campus)
Granrath, R. E. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Carmona Iragui, María (Institut d'Investigació Biomèdica Sant Pau)
Wilkerson, R. B. (Department of Biochemistry and Molecular Genetics. University of Colorado Anschutz Medical Campus)
Kahn, D. E. (Linda Crnic Institute for Down Syndrome. University of Colorado Anschutz Medical Campus)
Joshi, M. (Functional Genomics Facility. University of Colorado Anschutz Medical Campus)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Blesa, Rafael (Institut d'Investigació Biomèdica Sant Pau)
Fortea, Juan (Institut d'Investigació Biomèdica Sant Pau)
D'Alessandro, A. (Department of Biochemistry and Molecular Genetics. University of Colorado Anschutz Medical Campus)
Costello, J. C. (Department of Pharmacology. University of Colorado Anschutz Medical Campus)
Sullivan, K. D. (Functional Genomics Facility. University of Colorado Anschutz Medical Campus)
Espinosa, J. M. (Department of Molecular. Cellular and Developmental Biology. University of Colorado Boulder)
Universitat Autònoma de Barcelona

Date:	2019
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.
Grants:	Instituto de Salud Carlos III PI17-01896 Instituto de Salud Carlos III PI14-1561 Instituto de Salud Carlos III PI18-00335 Instituto de Salud Carlos III PI14-01126 Instituto de Salud Carlos III PI16-01825 Instituto de Salud Carlos III PI13-01532 Instituto de Salud Carlos III PI17-01019
Note:	Altres ajuts: This work has also been supported by a "Marató TV3" grant (20141210 to J.F. and 044412 to R.B.).
Note:	Altres ajuts: PERIS/SLT006-17-00119
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Chromosome abnormality ; Immunological disorders ; Animals ; Biosynthetic Pathways ; Cell Line ; Chromosomes, Human, Pair 21 ; Cytokines ; Down Syndrome ; Gene Expression ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Kynurenine ; Metabolomics ; Mice, Inbred C57BL ; Quinolinic Acid ; Receptors, Interferon ; Trisomy
Published in:	Nature communications, Vol. 10 Núm. 1 (january 2019) , p. 4766, ISSN 2041-1723

DOI: 10.1038/s41467-019-12739-9
PMID: 31628327

11 p, 871.5 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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