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JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome.
Tuttle, Kathryn D; Waugh, Katherine A; Araya, Paula; Minter, Ross; Orlicky, David J; Ludwig, Michael; Andrysik, Zdenek; Burchill, Matthew A; Tamburini, Beth A J; Sempeck, Colin; Smith, Keith; Granrath, Ross; Tracy, Dayna; Baxter, Jessica; Espinosa, Joaquin M; Sullivan, Kelly D.
  • Tuttle KD; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Waugh KA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Araya P; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Minter R; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Orlicky DJ; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Ludwig M; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Andrysik Z; 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.
  • Burchill MA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Tamburini BAJ; 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.
  • Sempeck C; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Smith K; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Granrath R; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Tracy D; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Baxter J; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Espinosa JM; 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.
  • Sullivan KD; 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.
Cell Rep ; 33(7): 108407, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-927290
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sulfonamides / Azetidines / Down Syndrome / Protein Kinase Inhibitors / Janus Kinase 1 / Janus Kinase 2 / Hypersensitivity Type of study: Prognostic study Topics: Long Covid Limits: Animals Language: English Journal: Cell Rep Year: 2020 Document Type: Article Affiliation country: J.celrep.2020.108407

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sulfonamides / Azetidines / Down Syndrome / Protein Kinase Inhibitors / Janus Kinase 1 / Janus Kinase 2 / Hypersensitivity Type of study: Prognostic study Topics: Long Covid Limits: Animals Language: English Journal: Cell Rep Year: 2020 Document Type: Article Affiliation country: J.celrep.2020.108407