Journal article
Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency
- Abstract:
- Background Inflammatory phenomena such as hyperinflammation or hemophagocytic lymphohistiocytosis are a frequent yet paradoxical accompaniment to virus susceptibility in patients with impairment of type I interferon (IFN-I) signaling caused by deficiency of signal transducer and activator of transcription 2 (STAT2) or IFN regulatory factor 9 (IRF9). Objective We hypothesized that altered and/or prolonged IFN-I signaling contributes to inflammatory complications in these patients. Methods We explored the signaling kinetics and residual transcriptional responses of IFN-stimulated primary cells from individuals with complete loss of one of STAT1, STAT2, or IRF9 as well as gene-edited induced pluripotent stem cell–derived macrophages. Results Deficiency of any IFN-stimulated gene factor 3 component suppressed but did not abrogate IFN-I receptor signaling, which was abnormally prolonged, in keeping with insufficient induction of negative regulators such as ubiquitin-specific peptidase 18 (USP18). In cells lacking either STAT2 or IRF9, this late transcriptional response to IFN-α2b mimicked the effect of IFN-γ. Conclusion Our data suggest a model wherein the failure of negative feedback of IFN-I signaling in STAT2 and IRF9 deficiency leads to immune dysregulation. Aberrant IFN-α receptor signaling in STAT2- and IRF9-deficient cells switches the transcriptional output to a prolonged, IFN-γ–like response and likely contributes to clinically overt inflammation in these individuals.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 4.8MB, Terms of use)
-
- Publisher copy:
- 10.1016/j.jaci.2022.01.026
Authors
- Publisher:
- Elsevier
- Journal:
- Journal of Allergy and Clinical Immunology More from this journal
- Volume:
- 150
- Issue:
- 4
- Pages:
- 955-964.E16
- Publication date:
- 2022-02-16
- Acceptance date:
- 2022-01-14
- DOI:
- EISSN:
-
1097-6825
- ISSN:
-
0091-6749
- Pmid:
-
35182547
- Language:
-
English
- Keywords:
- Pubs id:
-
1241519
- Local pid:
-
pubs:1241519
- Deposit date:
-
2022-04-11
- ARK identifier:
Terms of use
- Copyright holder:
- Gothe et al.
- Copyright date:
- 2022
- Rights statement:
- Copyright 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record