Defining the role of interferon signaling in mouse models of Down syndrome

Abstract

Abstract Down syndrome (DS) is caused by triplication of chromosome 21 (chr21) and is the most common chromosomal abnormality (1/700 live births). Our lab recently identified interferons (IFNs) as a core signaling pathway hyperactivated among diverse lineages of primary immune cells from individuals with DS. Notably, four of the six IFN receptor (IFNR) subunits for Types I, II, and III IFNs are encoded on chr21. Heightened IFN signaling in the disomic population is associated with developmental defects, cognitive impairments, and autoimmunity, a clinical profile highly similar to individuals with DS. However, the relationship between IFN signaling and such phenotypes has not been investigated in DS. We stimulated three different mouse models of DS with toll-like receptor (TLR) agonists, which potently induce interferon production. Both chronic and acute administration of TLR agonists caused lethal hyperresponsiveness only in the DS strain that harbors three copies of the IFNR locus. The resulting inflammation impacts multiple organ systems. This observation has profound implications for understanding how people with DS may differentially experience inflammation in response to infection during their lifetime. These studies represent the first steps in establishing a causative relationship between IFN signaling and DS-associated immune dysfunction to identify potential therapeutic targets for improving health outcomes in DS.