Tuttle, Kathryn DWaugh, Katherine AAraya, PaulaMinter, RossOrlicky, David JLudwig, MichaelAndrysik, ZdenekBurchill, Matthew ATamburini, Beth A JSempeck, ColinSmith, KeithGranrath, RossTracy, DaynaBaxter, JessicaEspinosa, Joaquin MSullivan, Kelly D
Summary
Interferons are proteins secreted by cells as a response to viruses and other substances. Down syndrome (DS) patients experience something called heightened interferon signaling. This causes an ongoing inflammation throughout the body that is thought to contribute to many of the complications faced by those with DS. Researchers used established DS mouse models to assess additional interferon interactions. The results of their work indicate that stimuli that normally induce interferon in the general population causes harmful hyperinflammation in those with DS. The observed positive results from the use of inhibitors such as JAK1. This is of particular importance because inflammation caused by acute illnesses such as a SARS-CoV-2 infection could also be mediated with JAK1.
Abstract
Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.
Conditions
COVID-19, Hypersensitivity, Infections, Inflammation, Liver Diseases, Weight Loss