Enhanced type I interferon signature induces neutrophil extracellular traps enriched in mitochondrial DNA in adult-onset Still's disease
Enhanced type I interferon signature induces neutrophil extracellular traps enriched in mitochondrial DNA in adult-onset Still's disease
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DOI：
10.1016/j.jaut.2022.102793
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发表时间：
2022-02-02
影响因子：
12.8
通讯作者：
Hu, Qiongyi
中科院分区：
文献类型：
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作者：
Ma, Yuning;Wang, Mengyan;Hu, Qiongyi
成人斯蒂尔病（AOSD）是一种罕见但临床上众所周知的自身炎症性疾病。细胞因子风暴是AOSD的标志，由中性粒细胞过度活化和增强的中性粒细胞胞外陷阱（NET）形成介导。I型干扰素（IFN）在促炎症反应的起始中具有主要作用，可诱导随后的炎性细胞因子产生。然而，I型IFN在AOSD中的作用尚不清楚。事实上，AOSD患者呈现高水平的IFN-α和IFN-β表达。在这项研究中，对IFN-α和IFN-β数据进行了分层无监督聚类，以确定一组患有严重疾病的AOSD患者。来自未经治疗的活动性AOSD患者的中性粒细胞在其IFN-α应答中显示出非常强的富集，如通过RNA-seq所示并通过IFN评分所证实。还测试了IFN-α是否刺激NET形成。IFN-α具有形成含有氧化线粒体DNA（ox-mtDNA）的NET的能力。此外，JAK抑制剂可用于抑制I型IFN诱导的NET形成并最终控制ox-mtDNA释放。我们的研究结果表明，在AOSD的发病机制中的重要作用，I型干扰素通过促进NET的形成，其特点是ox-mtDNA的水平提高。这些发现为AOSD的治疗方法开辟了新的研究途径。
Adult-onset Still's disease (AOSD) is a rare but clinically well-known auto-inflammatory disorder. Cytokine storm, the hallmark of AOSD, is mediated by neutrophil hyperactivation and enhanced neutrophil extracellular trap (NET) formation. Type I interferons (IFNs), having a primary role in the initiation of proinflammation responses, can induce subsequent inflammatory cytokine production. However, the role of type I IFNs in AOSD is unclear. Indeed, high levels of IFN-alpha and IFN-beta expression are presented by AOSD patients. In this investigation, hierarchical unsupervised clustering was performed on IFN-alpha and IFN-beta data to identify a cluster of AOSD patients who had a serious condition. Neutrophils from treatment-naive active AOSD patients showed very strong enrichment in their IFN-alpha response, as shown by RNA-seq and confirmed by the IFN score. Whether IFN-alpha stimulates NET formation was also tested. IFN-alpha had the ability to form NETs that contained oxidized mitochondrial DNA (ox-mtDNA). Moreover, the JAK inhibitor could be used to dampen type I IFN-induced NET formation and eventually control ox-mtDNA release. Our results demonstrated the important roles of type I IFNs in the pathogenesis of AOSD through their promotion of NET formation, as characterized by the enhanced level of ox-mtDNA. The findings open up new avenues of research into therapeutic approaches for AOSD.