2. Academic Validation
  3. JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome

JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome

  • Cell Rep. 2020 Nov 17;33(7):108407. doi: 10.1016/j.celrep.2020.108407.
Kathryn D Tuttle 1,  Katherine A Waugh 1,  Paula Araya 1,  Ross Minter 1,  David J Orlicky 2,  Michael Ludwig 1,  Zdenek Andrysik 3,  Matthew A Burchill 4,  Beth A J Tamburini 5,  Colin Sempeck 1,  Keith Smith 1,  Ross Granrath 1,  Dayna Tracy 1,  Jessica Baxter 1,  Joaquin M Espinosa 6,  Kelly D Sullivan 7
Affiliations

Affiliations

  • 1 Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 2 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 3 Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 4 Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 5 Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 6 Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: joaquin.espinosa@cuanschutz.edu.
  • 7 Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: kelly.d.sullivan@cuanschutz.edu.
PMID: 33207208 DOI: 10.1016/j.celrep.2020.108407
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.

Keywords

Down syndrome; JAK inhibitors; autoimmunity; autoinflammation; cytokine storm; immune system; immune therapy; interferon; liver disease; trisomy 21.

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