Enhanced type I interferon signature induces neutrophil extracellular traps enriched in mitochondrial DNA in adult-onset Still's disease
Yuning Ma, Mengyan Wang, Jinchao Jia, Jianfen Meng, Jialin Teng, Dehao Zhu, Hui Shi, Yue Sun, Yutong Su, Honglei Liu, Xiaobing Cheng, Junna Ye, Huihui Chi, Tingting Liu, Xia Chen, Liyan Wan, Zhuochao Zhou, Fan Wang, Dongyi He, Chengde Yang, Qiongyi Hu
Abstract
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-α and IFN-β expression are presented by AOSD patients. In this investigation, hierarchical unsupervised clustering was performed on IFN-α and IFN-β data to identify a cluster of AOSD patients who had a serious condition. Neutrophils from treatment-naïve active AOSD patients showed very strong enrichment in their IFN-α response, as shown by RNA-seq and confirmed by the IFN score. Whether IFN-α stimulates NET formation was also tested. IFN-α 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.