5-oxoETE promote thrombosis in antiphospholipid syndrome by triggering NETs formation through PLC/PKC/ERK pathway.

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-10-08 DOI:10.1007/s00011-024-01956-8
Xiaodong Song, Xufeng Chen, Dong Wang, Jie Bai
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Abstract

Background: One mechanism by which antiphospholipid syndrome (APS) IgG contribute to thrombotic events in patients with APS is through the potentiation of neutrophil extracellular traps (NETs) release. However, the exact mechanism by which APS IgG induces NETs formation and thrombosis has not been fully elucidated.

Methods: We conducted untargeted metabolomics on serum samples from thrombotic APS patients to identify metabolic changes. The effect of 5-oxoETE on NETs formation and oxidative stress was evaluated in vitro by treating neutrophils with various concentrations of 5-oxoETE. The involvement of the PLC/PKC/ERK signaling pathway in 5-oxoETE-induced NETs formation was examined using pharmacological inhibitors. In vivo, we assessed the effects of inhibiting 5-oxoETE synthesis or blocking its receptor (OXE-R) on NETs formation and thrombosis in APS mouse models.

Results: Serum metabolomics revealed significantly elevated levels of 5-oxoETE in APS patients. In vitro experiments demonstrated that 5-oxoETE, via OXE-R activation of the PLC/PKC/ERK signaling pathway, increased NETs formation and oxidative stress in a dose-dependent manner. In vivo, inhibiting 5-oxoETE synthesis or OXE-R reduced NETs formation and attenuated venous thrombosis in APS mice models.

Conclusion: This study identifies 5-oxoETE as a critical mediator of NET formation and thrombosis in APS. Targeting 5-oxoETE or OXE-R may offer a promising therapeutic approach for thrombotic APS and other NET-associated autoimmune diseases.

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5-oxoETE 通过 PLC/PKC/ERK 途径触发 NETs 的形成,从而促进抗磷脂综合征的血栓形成。
背景:抗磷脂综合征(APS)IgG导致APS患者血栓事件的机制之一是通过促进中性粒细胞胞外捕获物(NETs)的释放。然而,APS IgG诱导NETs形成和血栓形成的确切机制尚未完全阐明:我们对血栓性 APS 患者的血清样本进行了非靶向代谢组学研究,以确定代谢变化。通过用不同浓度的 5-oxoETE 处理中性粒细胞,在体外评估了 5-oxoETE 对 NETs 形成和氧化应激的影响。使用药理抑制剂检测了 PLC/PKC/ERK 信号通路在 5-oxoETE 诱导的 NETs 形成中的参与情况。在体内,我们评估了抑制 5-oxoETE 合成或阻断其受体(OXE-R)对 APS 小鼠模型中 NETs 形成和血栓形成的影响:结果:血清代谢组学显示,APS 患者的 5-oxoETE 水平明显升高。体外实验表明,5-oxoETE 通过 OXE-R 激活 PLC/PKC/ERK 信号通路,以剂量依赖的方式增加了 NETs 的形成和氧化应激。在体内,抑制 5-oxoETE 合成或 OXE-R 可减少 APS 小鼠模型中 NETs 的形成并减轻静脉血栓形成:本研究发现 5-oxoETE 是 APS 中 NET 形成和血栓形成的关键介质。针对5-oxoETE或OXE-R可能为血栓性APS和其他NET相关自身免疫性疾病提供一种有前景的治疗方法。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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