Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency - 04/10/22
, Sophie Hambleton, DPhil a, g, ⁎ 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.
Il testo completo di questo articolo è disponibile in PDF.Key words : Type I interferon, antiviral immunity, ISGF3, HLH, type II interferon, GAF, STAT2, IRF9
Abbreviations used : CRISPR, EBV, GAF, GAS, HLH, ICAM1, IFNAR, IFN-I, iPS, IRF9, ISG, ISGF3, JAK, KO, LCL, mRNA, p, PBS, SOCS, USP18, WT
Mappa
| The last 2 authors contributed equally to this article, and both should be considered senior author. |
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| The Nanostring data set generated and analyzed during the current study is available from the corresponding author on request. |
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| F. Gothe is supported by the Munich Clinician Scientist Program at LMU (FoeFoLeplus) and has received fellowships from the Bubble Foundation and the Care-for-Rare Foundation. C. F. Hatton is funded by an MRC studentship (MR/N013840/1). F. Hauck is funded by the Else Kröner-Fresenius Stiftung (EKFS, 2017_A110) and the German Federal Ministry of Education and Research (BMBF, 01GM1910C). S. Hambleton and C. J. A. Duncan are funded by the Wellcome Trust (207556/Z/17/Z and 211153/Z/18/Z respectively). |
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| Disclosure of potential conflict of interest: S. Hambleton declares honoraria from CSL Behring and Takeda for teaching and consultancy. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 150 - N° 4
P. 955 - ottobre 2022 Ritorno al numero
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