STI NG-associated vasculopathy develops independently of IRF3 in mice

James D. Warner, Ricardo A. Irizarry-Caro, Brock G. Bennion, Teresa L. Ai, Amber M. Smith, Cathrine A. Miner, Tomomi Sakai, Vijay K. Gonugunta, Jianjun Wu, Derek J. Platt, Nan Yan, Jonathan J. Miner

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Patients with stimulator of interferon genes (STI N G)-associated vasculopathy with onset in infancy (SAVI) develop systemic inflammation characterized by vasculopathy, interstitial lung disease, ulcerative skin lesions, and premature death. Autosomal dominant mutations in STI N G are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)- stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STI N G N153S knock-in mice as a model of SAVI. These mice spontaneously developed inflammation within the lung, hypercytokinemia, T cell cytopenia, skin ulcerations, and premature death. Cytometry by time-of-flight (CyTO F) analysis revealed that the STI N G N153S mutation caused myeloid cell expansion, T cell cytopenia, and dysregulation of immune cell signaling. Unexpectedly, we observed only mild up-regulation of ISGs in STI N G N153S fibroblasts and splenocytes and STI N G N154S SAVI patient fibroblasts. STI N G N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STI N G N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice.

Original languageEnglish (US)
Pages (from-to)3279-3292
Number of pages14
JournalJournal of Experimental Medicine
Volume214
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Warner, J. D., Irizarry-Caro, R. A., Bennion, B. G., Ai, T. L., Smith, A. M., Miner, C. A., Sakai, T., Gonugunta, V. K., Wu, J., Platt, D. J., Yan, N., & Miner, J. J. (2017). STI NG-associated vasculopathy develops independently of IRF3 in mice. Journal of Experimental Medicine, 214(11), 3279-3292. https://doi.org/10.1084/jem.20171351