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

24 Citations (Scopus)

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

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Sexually Transmitted Diseases
Interferons
Genes
Premature Mortality
Myeloid Cells
T-Lymphocytes
Mutation
Lung Diseases
Gene Knock-In Techniques
Up-Regulation
Fibroblasts
Skin
Interstitial Lung Diseases
Pneumonia
Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Warner, J. D., Irizarry-Caro, R. A., Bennion, B. G., Ai, T. L., Smith, A. M., Miner, C. A., ... 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

STI NG-associated vasculopathy develops independently of IRF3 in mice. / Warner, James D.; Irizarry-Caro, Ricardo A.; Bennion, Brock G.; Ai, Teresa L.; Smith, Amber M.; Miner, Cathrine A.; Sakai, Tomomi; Gonugunta, Vijay K.; Wu, Jianjun; Platt, Derek J.; Yan, Nan; Miner, Jonathan J.

In: Journal of Experimental Medicine, Vol. 214, No. 11, 01.11.2017, p. 3279-3292.

Research output: Contribution to journalArticle

Warner, JD, Irizarry-Caro, RA, Bennion, BG, Ai, TL, Smith, AM, Miner, CA, Sakai, T, Gonugunta, VK, Wu, J, Platt, DJ, Yan, N & Miner, JJ 2017, 'STI NG-associated vasculopathy develops independently of IRF3 in mice', Journal of Experimental Medicine, vol. 214, no. 11, pp. 3279-3292. https://doi.org/10.1084/jem.20171351
Warner JD, Irizarry-Caro RA, Bennion BG, Ai TL, Smith AM, Miner CA et al. STI NG-associated vasculopathy develops independently of IRF3 in mice. Journal of Experimental Medicine. 2017 Nov 1;214(11):3279-3292. https://doi.org/10.1084/jem.20171351
Warner, James D. ; Irizarry-Caro, Ricardo A. ; Bennion, Brock G. ; Ai, Teresa L. ; Smith, Amber M. ; Miner, Cathrine A. ; Sakai, Tomomi ; Gonugunta, Vijay K. ; Wu, Jianjun ; Platt, Derek J. ; Yan, Nan ; Miner, Jonathan J. / STI NG-associated vasculopathy develops independently of IRF3 in mice. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 11. pp. 3279-3292.
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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.",
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