JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome.
Animals
Azetidines
/ therapeutic use
Down Syndrome
/ complications
Female
Hypersensitivity
/ drug therapy
Immunity, Innate
Interferon-alpha
/ metabolism
Janus Kinase 1
/ antagonists & inhibitors
Janus Kinase 2
/ antagonists & inhibitors
Liver
/ immunology
Male
Mice
Mice, Inbred C57BL
Protein Kinase Inhibitors
/ therapeutic use
Purines
Pyrazoles
Sulfonamides
/ therapeutic use
Toll-Like Receptors
/ metabolism
Down syndrome
JAK inhibitors
autoimmunity
autoinflammation
cytokine storm
immune system
immune therapy
interferon
liver disease
trisomy 21
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
17 11 2020
17 11 2020
Historique:
received:
14
05
2020
revised:
21
09
2020
accepted:
28
10
2020
entrez:
18
11
2020
pubmed:
19
11
2020
medline:
15
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33207208
pii: S2211-1247(20)31396-6
doi: 10.1016/j.celrep.2020.108407
pmc: PMC7727402
mid: NIHMS1647637
pii:
doi:
Substances chimiques
Azetidines
0
Interferon-alpha
0
Protein Kinase Inhibitors
0
Purines
0
Pyrazoles
0
Sulfonamides
0
Toll-Like Receptors
0
Jak1 protein, mouse
EC 2.7.10.2
Jak2 protein, mouse
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
baricitinib
ISP4442I3Y
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108407Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK125595
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA190216
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150305
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145988
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI155474
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI121209
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests K.D.T., K.A.W., K.D.S., and J.M.E. are co-inventors on two patents related to JAK inhibition: U.S. Provisional Patent Application Serial No. 62/992,855 entitled “JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19” and U.S. Provisional Patent Application Serial No. 62/993,749 entitled “Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia.” J.M.E. currently serves on the COVID Development Advisory Board for Elly Lilly, the manufacturer of baricitinib, and on the Cell Reports Advisory Board.
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