tRF-His-GTG-1 通过细胞外囊泡增强狼疮中的 NETs 形成和干扰素-α产生。
tRF-His-GTG-1 enhances NETs formation and interferon-α production in lupus by extracellular vesicle.
机构信息
Department of Medical Research, Taichung Veterans General Hospital, No.1650, Sec.4, Taiwan Boulevard, Xitun Dist, Taichung, 40705, Taiwan.
Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 40227, Taiwan.
出版信息
Cell Commun Signal. 2024 Jul 7;22(1):354. doi: 10.1186/s12964-024-01730-7.
BACKGROUND
Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE.
METHODS
We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay.
RESULTS
Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P < 0.005). We demonstrated that SLE patient-derived immune complexes (ICs) induced platelet activation, followed by pEVs release. ICs-triggered NETs formation was significantly enhanced in the presence of pEVs through Toll-like receptor (TLR) 8 activation. Increased levels of tRF-His-GTG-1 in pEVs and neutrophils of SLE patients were associated with disease activity. tRF-His-GTG-1 interacted with TLR8 to prime p47phox phosphorylation in neutrophils, resulting in reactive oxygen species production and NETs formation. Additionally, tRF-His-GTG-1 modulated NF-κB and IRF7 activation in neutrophils upon TLR8 engagement, resulting IL-1β, IL-8, and interferon-α upregulation, respectively.
CONCLUSIONS
The level of tRF-His-GTG-1 was positively correlated with NETs formation in SLE patients; tRF-His-GTG-1 inhibitor could efficiently suppress ICs-triggered NETs formation/hyperactivation, which may become a potential therapeutic target.
背景
活性严重全身性红斑狼疮（SLE）中，过度活跃的中性粒细胞细胞外陷阱（NETs）形成起着关键作用。然而，导致 SLE 中失调的 NETs 形成失衡的原因尚不清楚。转移 RNA 衍生的小 RNA（tsRNAs）是新型非编码 RNA，参与多种细胞过程。我们探讨了 tsRNAs 在 SLE 中对 NETs 形成的作用。
方法
我们分析了 50 名 SLE 患者和 20 名健康对照者的 NETs DNA 和血小板衍生的细胞外囊泡（pEVs）水平。通过免疫荧光测定和髓过氧化物酶-DNA PicoGreen 测定评估 pEVs 对 NETs 形成的影响。通过体外基于细胞的测定研究 pEVs 对 NETs 形成和炎症细胞因子产生的调节机制。
结果
SLE 患者的循环 NETs DNA 和 pEVs 增加，并与疾病活动相关（P<0.005）。我们证明了 SLE 患者来源的免疫复合物（ICs）诱导血小板活化，随后释放 pEVs。在 pEVs 存在的情况下，通过 Toll 样受体（TLR）8 激活，ICs 触发的 NETs 形成显著增强。SLE 患者的 pEVs 和中性粒细胞中 tRF-His-GTG-1 水平增加与疾病活动相关。tRF-His-GTG-1 与 TLR8 相互作用，导致中性粒细胞中 p47phox 磷酸化，从而产生活性氧物质和 NETs 形成。此外，tRF-His-GTG-1 在 TLR8 结合时调节中性粒细胞中 NF-κB 和 IRF7 的激活，分别导致 IL-1β、IL-8 和干扰素-α的上调。
结论
tRF-His-GTG-1 的水平与 SLE 患者的 NETs 形成呈正相关；tRF-His-GTG-1 抑制剂可有效抑制 ICs 触发的 NETs 形成/过度激活，这可能成为一种潜在的治疗靶点。
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