Powers, Rani KCulp-Hill, RachelLudwig, Michael PSmith, Keith PWaugh, Katherine AMinter, RossTuttle, Kathryn DLewis, Hannah CRachubinski, Angela LGranrath, Ross ECarmona-Iragui, MaríaWilkerson, Rebecca BKahn, Darcy EJoshi, MolishreeLleó, AlbertoBlesa, RafaelFortea, JuanD'Alessandro, AngeloCostello, James CSullivan, Kelly DEspinosa, Joaquin M
Summary
Down syndrome (DS) affects immune and neurological function. It is known that Down syndrome is caused by Trisomy 21, but the mechanisms behind the syndrome are still unclear. Researchers seek to better understand DS through a large metabolomics study of plasma and cerebrospinal fluid. This showed that DS produced elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Researchers used insights gained through the metabolic study to observe KP regulation in a mouse model of DS. These results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
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.
Conditions
Trisomy