Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
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DOI：
10.1038/s41467-019-12739-9
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发表时间：
2019-10-18
影响因子：
16.6
通讯作者：
Espinosa, Joaquin M.
中科院分区：
文献类型：
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作者：
Powers, Rani K.;Culp-Hi, Rachel;Espinosa, Joaquin M.
21三体(T21)导致唐氏综合征(DS)，通过不明确的机制影响免疫和神经功能。在这里，我们报告了一项针对血浆和脑脊液的大型代谢组学研究，在独立的队列中显示，DS患者会产生高水平的犬尿氨酸和喹啉酸，这两种色氨酸分解代谢产物分别具有强大的免疫抑制和神经毒性特性。DS患者的免疫细胞过度表达IDO1，这是犬尿氨酸途径(KP)中的限速酶，也是一种已知的干扰素(干扰素)刺激基因。此外，干扰素诱导的细胞因子水平与KP失调呈正相关。利用代谢示踪分析，我们发现21号染色体上编码的干扰素受体的过度表达有助于增强干扰素的刺激，从而导致T21细胞中IDO1的过度表达和犬尿氨酸的过度产生。最后，携带干扰素受体三倍体的DS小鼠模型表现出KP失调。综上所述，我们的结果揭示了T21可能导致DS的免疫抑制和神经毒性的机制。
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.