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

Autor: Song X; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.; Department of Neurology, Peking University People's Hospital, Beijing, China., Chen X; Department of Neurology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Wang D; Department of Neurology, Peking University People's Hospital, Beijing, China., Bai J; Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China. docbai@yeah.net.
Jazyk: angličtina
Zdroj: Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2024 Dec; Vol. 73 (12), pp. 2165-2177. Date of Electronic Publication: 2024 Oct 08.
DOI: 10.1007/s00011-024-01956-8
Abstrakt: 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.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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