期刊
ARTHRITIS RESEARCH & THERAPY
卷 21, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13075-018-1800-z
关键词
Adult-onset Still's disease; Neutrophil extracellular traps; NLRP3 inflammasome; Macrophages
类别
资金
- National Natural Science Foundation of China [81671589, 81601400]
- Shanghai Sailing Program [16YF1407000, 18YF1414500, 18YF1414100]
- Science and Technology Commission of Shanghai Municipality [17411965100]
- Prairie fire program [LYJH-358]
BackgroundAdult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by neutrophilia and NLRP3 inflammasome and macrophage activation. We investigated the role of neutrophil extracellular traps (NETs) in the pathogenesis of AOSD, and explored the effect of NETs on activating NLRP3 inflammasome and proinflammatory macrophages.MethodsThe sera of 73 AOSD patients and 40 healthy controls were used to detect the level of cell-free DNA and NET-DNA complexes. NET formation ex vivo was analyzed using immunofluorescence and flow plates. The activation of NLRP3 inflammasome in THP-1 cells and proinflammatory macrophages stimulated with DNA purified from NETs was measured using RT-PCR, ELISA, Western blotting and flow cytometry.ResultsThe levels of cell-free DNA and NET-DNA complexes were significantly increased in the circulation of patients with AOSD compared with healthy controls, and freshly isolated neutrophils from patients with AOSD were predisposed to high levels of spontaneous NET release. Interestingly, enhanced NET release was abrogated with NADPH oxidase inhibitors and a mitochondrial scavenger. Furthermore, DNA purified from AOSD NETs activated NLRP3 inflammasomes. NET DNA from AOSD also exerted a potent capacity to accelerate the activation of CD68(+)CD86(+) macrophages and increased the expression of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-. Finally, the copy number of mitochondrial DNA (mtDNA) in NETs and plasma was significantly increased in AOSD patients, suggesting that mtDNA may be involved in the activation of NLRP3 and inflammatory macrophages.ConclusionsThese findings implicate accelerated NET formation in AOSD pathogenesis through activation of NLRP3 and proinflammatory macrophages, and identify a novel link between neutrophils and macrophages by NET formation in AOSD.
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