中性粒细胞来源的无细胞 DNA 可触发视神经脊髓炎谱系障碍中的 I 型干扰素特征。
Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder.
机构信息
From the Department of Neurology (Hisashi Murata, M.K., Y.Y., S.B., N.S., Y.S., K.K., S.T., T.K., T.O., Hideki Mochizuki), Graduate School of Medicine, Osaka University; Department of Experimental Immunology (Y.Y.), WPI Immunology Frontier Research Center, Osaka University; Integrated Frontier Research for Medical Science Division (Y.Y., D.M., A.K., Hideki Mochizuki), Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University; Genome Information Research Center (D.M.), Research Institute for Microbial Diseases, Osaka University; and Department of Respiratory Medicine and Clinical Immunology (H.K., H.T., A.K.), Graduate School of Medicine, Osaka University, Suita, Japan.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2022 Feb 24;9(3). doi: 10.1212/NXI.0000000000001149. Print 2022 May.
BACKGROUND AND OBJECTIVES
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
背景与目的
最近越来越多的证据表明，1 型干扰素（IFN-1）特征在视神经脊髓炎谱系疾病（NMOSD）的发病机制中起关键作用。然而，增强 NMOSD 外周免疫系统中 IFN-1 途径的初始触发因素的机制仍有待阐明。
方法
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。体外评估血清无细胞 DNA（cfDNA）对外周血单核细胞（PBMC）中 IFN-1 的诱导作用，并结合 DNA 传感器阻断。通过亚硫酸氢盐测序分析 cfDNA 片段的 DNA 甲基化谱，阐明 cfDNA 的细胞来源。进一步分析 NMOSD 和对照组中性粒细胞细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。
结果
在 LL37 抗菌肽辅助下，从 NMOSD 中提取的 cfDNA 可增强 IFN-1 的诱导。DNase 处理、cGAS 抑制剂和 Toll 样受体 9 拮抗剂可有效抑制 IFN-1 的产生。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。全血转录组分析还揭示了 NMOSD 中的中性粒细胞激活。此外，NMOSD 来源的血清可增强 NETosis 的诱导，并用双嘧达莫有效抑制 NETosis。
讨论
我们的研究强调了 cfDNA 在 NMOSD 中诱导 IFN-1 特征方面的先前未揭示的作用，并进一步表明 NMOSD 中有一个新的药物治疗靶点。
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