Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency.

The Journal of allergy and clinical immunology 2022 Oct

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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). We hypothesized that altered and/or prolonged IFN-I signaling contributes to inflammatory complications in these patients. 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. 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. 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. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Florian Gothe, Jarmila Stremenova Spegarova, Catherine F Hatton, Helen Griffin, Thomas Sargent, Sally A Cowley, William James, Anna Roppelt, Anna Shcherbina, Fabian Hauck, Hugh T Reyburn, Christopher J A Duncan, Sophie Hambleton. Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. The Journal of allergy and clinical immunology. 2022 Oct;150(4):955-964.e16