Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder.
Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder.
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DOI：
10.1212/nxi.0000000000001149
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发表时间：
2022-05
期刊：
影响因子：
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通讯作者：
Mochizuki H
中科院分区：
文献类型：
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作者：
Murata H;Kinoshita M;Yasumizu Y;Motooka D;Beppu S;Shiraishi N;Sugiyama Y;Kihara K;Tada S;Koda T;Konaka H;Takamatsu H;Kumanogoh A;Okuno T;Mochizuki H
近年来越来越多的证据表明，1型干扰素（IFN-1）信号在视神经肌萎缩症谱系障碍（NMOSD）的发病机制中起着关键作用。然而，在NMOSD的外周免疫系统中增强IFN-1途径的初始触发机制尚未阐明。从32名水通道蛋白-4抗体阳性NMOSD患者和23名健康受试者中获得临床样本。在体外结合DNA传感器的阻断评估了血清来源的无细胞DNA（cfDNA）在外周血单核细胞（PBMC）中的IFN-1诱导。通过亚硫酸氢盐测序分析cfDNA级分的DNA甲基化谱，阐明cfDNA的细胞起源。进一步分析NMOSD组和对照组中中性粒细胞胞外陷阱相关细胞死亡（NETosis）的诱导，并评估NETosis的药物干预效果。在具有LL 37抗微生物肽的辅因子的PBMC中观察到源自NMOSD的cfDNA对IFN-1的诱导增强。DNA酶处理、cGAS抑制剂和Toll样受体9拮抗剂有效地抑制IFN-1产生。NMOSD患者cfDNA的DNA甲基化模式表明cfDNA的主要细胞来源是中性粒细胞。全血转录组分析还显示NMOSD中的中性粒细胞活化。此外，用NMOSD衍生的血清观察到增强的NETosis诱导，并观察到双嘧达莫对NETosis的有效药理学抑制。我们的研究强调了先前未揭示的主要由嗜中性粒细胞释放的cfDNA在NMOSD中诱导IFN-1特征中的作用，并进一步表明了NMOSD中的新药理学靶标。
Recently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated. Clinical samples were obtained from 32 patients with aquaporin-4 antibody–positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed. Enhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed. Our study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.