STING-associated vasculopathy develops independently of IRF3 in mice
| Autor: | Tomomi Sakai, Nan Yan, James D. Warner, Brock G. Bennion, Cathrine A. Miner, Jianjun Wu, Teresa L. Ai, Ricardo A. Irizarry-Caro, Derek J. Platt, Jonathan J. Miner, Amber M. Smith, Vijay K. Gonugunta |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Myeloid T-Lymphocytes T cell Immunology Mice Transgenic Article 03 medical and health sciences 0302 clinical medicine Immune system Interferon hemic and lymphatic diseases Animals Humans Immunology and Allergy Medicine Vascular Diseases Lung Research Articles Cells Cultured Skin Inflammation Mice Knockout Cytopenia business.industry Interstitial lung disease Membrane Proteins Fibroblasts medicine.disease eye diseases 3. Good health Sting 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Stimulator of interferon genes Mutation Cytokines Interferon Regulatory Factor-3 business medicine.drug |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Warner et al. show that knock-in mice expressing a human disease–associated STING mutation spontaneously develop inflammatory lung and skin disease, hypercytokinemia, and T cell cytopenia, which occurs independently of IRF3. 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. |
| Databáze: | OpenAIRE |
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