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

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.

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

“…Recently, we reported an analogous activation of the IDO pathway in individuals with Trisomy 21 (Down syndrome) (29). Indeed, 4 of the 6 receptors for interferon-alpha and -gamma are encoded by genes on chromosome 21.…”

“…Interestingly, the major effects of COVID-19, in addition of IL-6 levels, were tryptophan metabolism and the kynurenine pathway. The rate-limiting step in this pathway is determined by the enzymatic activity of indole 2,3-dioxygenase (IDO1), a pleotropic enzyme with complex effects, including an immunoregulatory role (29). In general, the kynurenine/tryptophan ratio is a general measure of IDO activity, although the meaning of this measure alters depending upon the dynamics of metabolism and its effects on half-lives of kynurenine and tryptophan.…”

“…IDO1is a downstream target of interferon signaling (involving the STAT6 and NF-B pathways) (29), which is activated in response to viral infection (33). Intriguingly, however, type I interferon production is suppressed in SARS-COV-2 infection; in addition, multiple studies suggest that interferon gamma production correlates with disease severity (34)(35)(36)(37).…”

“…The newly identified RNA virus strain belongs to the Coronaviridae family and was referred to as '2019-nCoV'. (1) Phylogenetic analyses of the genome (29,903 nucleotides) demonstrated its similarity (89.1%) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that were previously isolated in bats in China (1).…”

JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy

“…We recently discovered that trisomy 21 (T21), the genetic cause of DS, causes consistent activation of the IFN transcriptional response in multiple cell types (12)(13)(14)(15), which is explained by the fact that four of the six IFN receptors are encoded on chromosome 21 (IFNAR1, IFNAR2, IFNGR2, IL10RB). Additional investigations of the proteome (16), metabolome (14), and immune cell lineages (13,15) of people with DS demonstrated that T21 causes: 1) changes in the circulating proteome indicative of chronic autoinflammation with clear dysregulation of IFN-inducible cytokines (16), 2) activation of the IFN-inducible kynurenine pathway, leading to elevated production of neurotoxic tryptophan catabolites (14), and 3) widespread hypersensitivity to IFN stimulation across the human immune system (13,15). Altogether, these results support the notion that DS can be understood in good measure as an interferonopathy, whereby increased IFN signaling could account for many of the developmental and clinical impacts of T21.…”