Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still's disease.
Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still's disease.
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中性粒细胞胞外诱捕网诱导的中间型单核细胞引发成人斯蒂尔病中的巨噬细胞活化综合征。
DOI：
10.1186/s12916-023-03231-9
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发表时间：
2023-12-20
期刊：
影响因子：
9.3
通讯作者：
Hu, Qiongyi
中科院分区：
文献类型：
--
作者：
Jia, Jinchao;Wang, Mengyan;Ma, Yuning;Meng, Jianfen;Zhu, Dehao;Chen, Xia;Shi, Hui;Sun, Yue;Liu, Honglei;Cheng, Xiaobing;Su, Yutong;Ye, Junna;Chi, Huihui;Liu, Tingting;Zhou, Zhuochao;Wang, Fan;Chen, Longfang;Yi, Da;Xiao, Yu;Yang, Chengde;Teng, Jialin;Hu, Qiongyi
成人发病斯蒂尔氏病（AOSD）是一种以先天免疫系统激活为特征的全身性自身炎症性疾病，具有巨噬细胞激活综合征（MAS）的高风险。MAS的发展与单核/巨噬细胞活化和细胞因子风暴有关。单核细胞由三个不同的亚群组成，经典单核细胞（CMs, CD14brightCD16−），中间单核细胞（IMs, CD14brightCD16 +）和非经典单核细胞（ncm, CD14dimCD16 +），每一个在炎症调节中都有不同的作用。然而，单核细胞亚群在AOSD患者中的频率和调节机制尚未确定。我们进行了流式细胞术、RNA测序、吞噬分析和酶联免疫吸附测定来评估单核细胞亚群、细胞功能和潜在的生物标志物。中性粒细胞胞外陷阱（NETs）对单核细胞的影响是通过评估DNA传感器mRNA水平、表面CD16表达和炎性小体途径激活来确定的。在活动性AOSD患者中发现了较高比例的中间单核细胞（IMs）。IMs中CD80、CD86、HLA-DR和CD163的表达高于CMs和ncm。在AOSD IMs中发现CD163上调，伴随着吞噬活性增加和细胞因子/趋化因子产生升高，包括IL-1β、IL-6、CCL8和CXCL10。IMs的频率与疾病活动度相关，在AOSD合并MAS的患者中更高。CCL8和CXCL10在AOSD-MAS患者单核细胞RNA测序中高表达，血浆CXCL10水平可作为AOSD-MAS的潜在生物标志物。此外，AOSD-MAS患者的单核细胞中dna传感通路被激活。来自AOSD的NETs刺激可诱导DNA传感器表达、IMs扩增和炎性体通路激活。这些影响可通过DNase I治疗消除。我们的研究结果表明，在AOSD中，IMs的比例升高，并与MAS相关。来自AOSD的NETs中的DNA成分在IMs的形成中发挥了重要作用，为治疗靶点提供了新的思路。在线版本包含补充材料，可在10.1186/s12916-023-03231-9获得。
Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14brightCD16 −), intermediate monocytes (IMs, CD14brightCD16 +), and non-classical monocytes (NCMs, CD14dimCD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified. We performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation. Higher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1β, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment. Our results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target. The online version contains supplementary material available at 10.1186/s12916-023-03231-9.
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