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Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target
Jason S. Knight, … , Daniel T. Eitzman, Amr H. Sawalha
Jason S. Knight, … , Daniel T. Eitzman, Amr H. Sawalha
Published September 21, 2017
Citation Information: JCI Insight. 2017;2(18):e93897. https://doi.org/10.1172/jci.insight.93897.
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Research Article

Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target

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Abstract

Antiphospholipid antibodies, present in one-third of lupus patients, increase the risk of thrombosis. We recently reported a key role for neutrophils — neutrophil extracellular traps (NETs), in particular — in the thrombotic events that define antiphospholipid syndrome (APS). To further elucidate the role of neutrophils in APS, we performed a comprehensive transcriptome analysis of neutrophils isolated from patients with primary APS. Moreover, APS-associated venous thrombosis was modeled by treating mice with IgG prepared from APS patients, followed by partial restriction of blood flow through the inferior vena cava. In patients, APS neutrophils demonstrated a proinflammatory signature with overexpression of genes relevant to IFN signaling, cellular defense, and intercellular adhesion. For in vivo studies, we focused on P-selectin glycoprotein ligand-1 (PSGL-1), a key adhesion molecule overexpressed in APS neutrophils. The introduction of APS IgG (as compared with control IgG) markedly potentiated thrombosis in WT mice, but not PSGL-1–KOs. PSGL-1 deficiency was also associated with reduced leukocyte vessel wall adhesion and NET formation. The thrombosis phenotype was restored in PSGL-1–deficient mice by infusion of WT neutrophils, while an anti–PSGL-1 monoclonal antibody inhibited APS IgG–mediated thrombosis in WT mice. PSGL-1 represents a potential therapeutic target in APS.

Authors

Jason S. Knight, He Meng, Patrick Coit, Srilakshmi Yalavarthi, Gautam Sule, Alex A. Gandhi, Robert C. Grenn, Levi F. Mazza, Ramadan A. Ali, Paul Renauer, Jonathan D. Wren, Paula L. Bockenstedt, Hui Wang, Daniel T. Eitzman, Amr H. Sawalha

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Figure 1

Functional gene network analysis of genes upregulated in neutrophils from patients with primary APS as compared with healthy matched controls.

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Functional gene network analysis of genes upregulated in neutrophils fro...
P values represent the significance of enrichment in the functional networks identified.

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