STING-associated vasculopathy develops independently of IRF3 in mice.

Autor:	Warner JD; Department of Medicine, Washington University School of Medicine, St. Louis, MO., Irizarry-Caro RA; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX., Bennion BG; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO., Ai TL; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO., Smith AM; Department of Medicine, Washington University School of Medicine, St. Louis, MO., Miner CA; Department of Medicine, Washington University School of Medicine, St. Louis, MO., Sakai T; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX., Gonugunta VK; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX., Wu J; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX., Platt DJ; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO., Yan N; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX nan.yan@utsouthwestern.edu.; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX., Miner JJ; Department of Medicine, Washington University School of Medicine, St. Louis, MO jonathan.miner@wustl.edu.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2017 Nov 06; Vol. 214 (11), pp. 3279-3292. Date of Electronic Publication: 2017 Sep 26.
DOI:	10.1084/jem.20171351
Abstrakt:	Patients with stimulator of interferon genes (STING)-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 STING are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)-stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STING 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 (CyTOF) analysis revealed that the STING 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 STING N153S fibroblasts and splenocytes and STING N154S SAVI patient fibroblasts. STING N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STING N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice. (© 2017 Warner et al.)
Databáze:	MEDLINE
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