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JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome
Kathryn D Tuttle1, Katherine A Waugh1, Paula Araya1
1Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
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.
Insights
Individuals with Down syndrome (DS) show overactive interferon signaling, leading to harmful inflammation. JAK1 inhibition may restore immune balance in DS patients, particularly during infections like SARS-CoV-2.
Area of Science:
- Immunology
- Genetics
- Down Syndrome Research
Background:
- Individuals with Down syndrome (DS) exhibit heightened interferon (IFN) signaling and chronic inflammation.
- This hyperactivation may stem from the extra copy of IFN receptor (IFNR) genes on chromosome 21.
- The clinical impact of IFN hyperactivity in DS is not well understood.
Purpose of the Study:
- To investigate the clinical effects of IFN hyperactivity in a mouse model of Down syndrome.
- To explore the potential of JAK1 inhibition as a therapeutic strategy for managing inflammation in DS.
Main Methods:
- Utilized a mouse model of DS that overexpresses IFNR genes.
- Administered a TLR3 agonist to induce chronic inflammation and observed immune responses.
- Assessed the impact of JAK1 inhibition on immune hypersensitivity and pathology.
Main Results:
- The DS mouse model demonstrated hypersensitivity to IFN ligands and overexpressed IFN-stimulated genes and cytokines upon TLR3 agonist treatment.
- Animals exhibited liver pathology and rapid weight loss due to induced chronic inflammation.
- JAK1 inhibition significantly reduced immune hypersensitivity, cytokine production, and associated pathology.
Conclusions:
- Down syndrome is associated with harmful hyperinflammation in response to IFN-inducing stimuli.
- JAK1 inhibition shows promise in restoring immune homeostasis in individuals with DS.
- This finding is relevant for managing inflammatory conditions, including SARS-CoV-2 infection, in the DS population.
