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Cited by 72interferon and immune responsesDown syndrome and intellectual disability researchImmune Response and Inflammation

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

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Tuttle, Kathryn D., Waugh, Katherine A., Araya, Paula, Minter, Ross, Orlicky, David J., Ludwig, Michael, Andrysik, Zdenek, Burchill, Matthew A. +8 more·2020·Cell Reports
DOI 10.1016/j.celrep.2020.108407PMC PMC7727402

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Abstract

Abstract Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence Summary Inhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.

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  • Both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation, which could exacerbate the neuroinflammatory response.

    “Notably, both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation,30,31,32,33,34,35,36,37,38,39,40 that could exacerbate the neuroinflammatory response.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [37]

    The Abstract reports IFN-signaling hyperactivation and chronic inflammation in individuals with DS, and the Results show that Dp16 mice are unusually responsive to IFN stimulation. But the Results also report no significant difference in basal pSTAT1 in Dp16 immune cells; the mouse findings therefore do not support describing IFN signaling as constitutively hyperactivated. The proposed neuroinflammatory consequence follows the citations and is not attributed to this source. (LLM, conf=0.88)

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  • Lethal immune hypersensitivity in Dp16 mice is blocked by JAK inhibition.

    “we reported that lethal immune hypersensitivity in Dp16 mice is blocked by JAK inhibition”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [37]

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Cited by

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Authors
Tuttle, K. D., Waugh, K. A., Araya, P., Minter, R., Orlicky, D. J., Ludwig, M., Andrysik, Z., Burchill, M. A., Tamburini, B. A. J., Sempeck, C., Smith, K., Granrath, R., Tracy, D., Baxter, J., Espinosa, J. M., & Sullivan, K. D.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
  • Espinosa, Joaquin M.
  • Sullivan, Kelly D.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-11
Volume
33
Issue
7
Pages
108407
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.108407
PMC
PMC7727402
OpenAlex
W3102865214
Cited by
72
References
8
Citations by year
2026: 13 · 2025: 11 · 2024: 17 · 2023: 7 · 2022: 9 · 2021: 9 · 2020: 6
FWCI
2.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
Down syndrome, JAK1 inhibition, interferon signaling, hypersensitivity, hyperinflammation, chronic inflammation, TLR3 agonist, IFN-stimulated genes, cytokine production, liver pathology, weight loss, immune homeostasis, COVID-19 pandemic
MeSH terms
Animals, Azetidines, Down Syndrome, Female, Hypersensitivity, Immunity, Innate, Liver, Male, Mice, Inbred C57BL, Purines, Pyrazoles, Sulfonamides, Interferon-alpha, Protein Kinase Inhibitors, Toll-Like Receptors, Mice, Janus Kinase 1, Janus Kinase 2

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