OC 46.1 - Neutrophil Adhesion-related S100A8/A9 and Neutrophil Extracellular Traps Production: A Vicious Cycle in Antiphospholipid Syndrome Thrombosis

Monday, June 24, 2024

14:45 – 15:00 ICT

Room: 111 A-C

Presenting Author(s)

Shengqiang Pei, PhD

Postdoctoral Researcher
Department of Laboratory Medicine, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital
Beijing, Beijing, China (People's Republic)

Co-Author(s)

wC

wen Chen

Postdoctoral Researcher
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Beijing, Beijing, China (People's Republic)
Dabuxilite Bayartaikishigtai

PhD Student
Department of Laboratory Medicine, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital
Beijing, Beijing, China (People's Republic)
YZ

Yang Zhang

Professor
Department of Laboratory Medicine, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital
Beijing, Beijing, China (People's Republic)
ZZ

Zhou Zhou

Professor
Department of Laboratory Medicine, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital
Beijing, Beijing, China (People's Republic)

Background: Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events. Previous studies have reported elevated levels of neutrophil extracellular traps (NETs) in the peripheral blood of patients with APS, however, our current comprehension of its underlying mechanisms remains insufficient.

Aims: To thoroughly investigate the mechanism of NETs overproduction in APS patients, and find potential targets for intervention.

Methods: We first confirmed the level of NETs and the distribution of neutrophils in thrombi in APS patients by using ELISA and immunostaining. Next, we performed single-cell transcriptome sequencing (scRNAseq) on leukocytes from APS patients. We also constructed animal models of APS and validated the scRNAseq results and potential therapeutic targets using multiple molecular techniques. Finally, we explored the molecular mechanisms of APS-associated NETs and thrombosis in vitro using immunostaining and multiple molecular techniques. Data are expressed as means ± standard error of the mean and a value of P≤0.05 was regarded to indicate statistical significance.

Results: We observed enhanced release of NETs and neutrophil adhesion in APS patients compared to healthy subjects, which may be related to endothelial damage. Additionally, scRNAseq results showed an increase in the expression of S100A8 and S100A9 in neutrophils from APS patients. Furthermore, the S100A8/A9 exhibited significant upregulation in APS patients and APS models. The use of the S100A8/A9 inhibitor, paquinimod, effectively reduced NETs and thrombosis in animal models. In vitro, the enhancement of neutrophil-endothelial adhesion has been shown to result in NETs production and the release of S100A8/A9 from APS neutrophils. Increased levels of S100A8/A9 stimulates the release of NETs, along with the release of S100A8/A9, creates a vicious cycle leading to thrombosis.

Conclusion(s): The study identifies a new mechanism of APS thrombosis and suggests that S100A8/A9 is a potential target for intervention in APS thrombosis.