IRF3 and type I interferons fuel a fatal response to myocardial infarction.
IRF3 and type I interferons fuel a fatal response to myocardial infarction.
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IRF3和I型干扰物为心肌梗死提供了致命的反应。
DOI：
10.1038/nm.4428
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发表时间：
2017-12
期刊：
影响因子：
82.9
通讯作者：
Weissleder R
中科院分区：
文献类型：
--
作者：
King KR;Aguirre AD;Ye YX;Sun Y;Roh JD;Ng RP Jr;Kohler RH;Arlauckas SP;Iwamoto Y;Savol A;Sadreyev RI;Kelly M;Fitzgibbons TP;Fitzgerald KA;Mitchison T;Libby P;Nahrendorf M;Weissleder R
干扰素调节因子3(IRF3)和I型干扰素(IFN)可预防感染和癌症，但IRF3的过度激活和I型干扰素的产生会导致Aicardi Goutieres综合征和婴儿刺痛相关血管病变(SAVI)等自体炎症条件。心肌梗死(MI)引起炎症，但MI相关炎症的主要分子驱动因素仍不清楚。在这里，我们表明，心脏中的缺血性细胞死亡通过激活IRF3和I型干扰素的产生而引发对心肌梗死的致命反应。在小鼠中，对从梗死区和非梗死区心脏分离的4,215个白细胞进行的单细胞RNA-Seq分析显示，MI可在一组不同的干扰素诱导细胞(被归类为心脏巨噬细胞的干扰素诱导细胞)中激发IRF3干扰素轴的激活。CGAS、其接头刺痛、I型干扰素受体IRF3或I型干扰素受体IFNAR基因缺陷的小鼠表现出干扰素刺激基因(ISG)的表达受损，在IRF3或IFNAR基因缺陷的小鼠中，与对照组相比，MI后的存活率提高。阻断IRF3依赖的信号转导通路，可减少心脏炎症细胞因子和趋化因子的表达，减少炎症细胞的浸润，从而抑制心室扩张，改善心功能。类似地，心肌梗死后用IFNAR中和抗体治疗小鼠可以消除干扰素反应，改善左心功能不全和存活率。这些结果证实IRF3和I型干扰素反应是心肌梗死后心肌保护的潜在治疗靶点。心肌梗死期间发生的大量细胞死亡释放自身DNA，并通过cGAS-STING-IRF3途径在渗透的白细胞中触发干扰素反应。在心肌梗死小鼠中，这一途径的遗传干扰或I型干扰素受体的抗体阻断改善了心功能和存活率。
Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause auto-inflammatory conditions such as Aicardi Goutieres Syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here, we show that ischemic cell death in the heart fuels a fatal response to myocardial infarction by activating IRF3 and type I IFN production. In mice, single cell RNA-Seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts revealed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon inducible cells (IFNICs that were classified as cardiac macrophages). Mice genetically deficient in cGAS, its adaptor STING, IRF3, or the type I interferon receptor IFNAR exhibited impaired interferon stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased cardiac inflammatory cell infiltration, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR neutralizing antibody after MI ablated the IFN response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I interferon response as a potential therapeutic target for post-MI cardioprotection. The massive cell death that occurs during myocardial infarction releases self-DNA and triggers an interferon response in infiltrating leukocytes via a cGAS-STING-IRF3 pathway. In mice subjected to myocardial infarction, genetic disrupton of this pathway or antibody blockade of the type I interferon receptor improved heart function and survival.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
影响因子：
5
作者：
Andersen, J.;VanScoy, S.;Reich, N. C.
通讯作者：
Reich, N. C.
影响因子：
15.9
作者：
Hanson, Melissa C.;Crespo, Monica R.;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
17.1
作者：
Fu J;Kanne DB;Leong M;Glickman LH;McWhirter SM;Lemmens E;Mechette K;Leong JJ;Lauer P;Liu W;Sivick KE;Zeng Q;Soares KC;Zheng L;Portnoy DA;Woodward JJ;Pardoll DM;Dubensky TW Jr;Kim Y
通讯作者：
Kim Y