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