STING-associated vasculopathy develops independently of IRF3 in mice.
STING-associated vasculopathy develops independently of IRF3 in mice.
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DOI：
10.1084/jem.20171351
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发表时间：
2017-11-06
期刊：
影响因子：
--
通讯作者：
Miner JJ
中科院分区：
文献类型：
--
作者：
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
华纳等人。研究表明，表达与人类疾病相关的刺痛突变的敲入小鼠会自发地发展为炎症性肺和皮肤病、高细胞分裂素血症和T细胞减少症，这些疾病独立于IRF3发生。患有婴儿起病的干扰素基因刺激物(STINT)相关血管病变(SAVI)的患者会出现全身性炎症，其特征是血管病变、间质性肺疾病、溃疡性皮肤病变和过早死亡。在SAVI患者中，STING的常染色体显性突变被认为触发了IRF3的激活和随后干扰素(干扰素)刺激基因(ISGs)的上调。我们建立了杂合子刺痛N153S敲入小鼠作为SAVI的模型。这些小鼠自发地出现肺部炎症、高细胞分裂素血症、T细胞减少、皮肤溃疡和过早死亡。飞行时间(CyTOF)分析表明，STINN153S突变可引起髓系细胞增殖、T细胞减少和免疫细胞信号转导失调。出乎意料的是，我们只观察到STINN153S成纤维细胞和脾细胞以及STINN154S SAVI患者成纤维细胞中ISGs的轻微上调。缺乏IRF3的STINN153S小鼠也会出现肺部疾病、髓系细胞扩张和T细胞减少。因此，SAVI相关的刺痛N153S突变触发IRF3非依赖性免疫细胞失调和小鼠肺部疾病。
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.
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影响因子：
3.7
作者：
Parikh BA;Beckman DL;Patel SJ;White JM;Yokoyama WM
通讯作者：
Yokoyama WM
DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
27.4
作者：
Eloranta, Maija-Leena;Franck-Larsson, Karin;Ronnblom, Lars
通讯作者：
Ronnblom, Lars
影响因子：
15.9
作者：
Jeremiah, Nadia;Neven, Benedicte;Rieux-Laucat, Frederic
通讯作者：
Rieux-Laucat, Frederic