Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

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  • Additional Information
    • Source:
      Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Society of Hematology, [2016]-
    • Subject Terms:
      Integrins*/metabolism ; Neutrophils*/metabolism ; Stroke*/metabolism ; Stroke*/etiology ; Vascular Cell Adhesion Molecule-1*/metabolism ; Venous Thrombosis*/metabolism ; Venous Thrombosis*/etiology; Animals ; Humans ; Male ; Mice ; Cell Adhesion ; Disease Models, Animal ; Mice, Knockout ; Neutrophil Activation
    • Abstract:
      Abstract: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.
      (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
    • Grant Information:
      R00 HL150233 United States HL NHLBI NIH HHS; R01 DK134011 United States DK NIDDK NIH HHS; R01 DK136685 United States DK NIDDK NIH HHS; R01 HL158546 United States HL NHLBI NIH HHS; R01 HL172846 United States HL NHLBI NIH HHS; R01 HL145753 United States HL NHLBI NIH HHS; P20 GM121307 United States GM NIGMS NIH HHS; R01 HL133497 United States HL NHLBI NIH HHS; R01 HL141155 United States HL NHLBI NIH HHS; T32 HL155022 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Integrins)
      0 (Vascular Cell Adhesion Molecule-1)
      0 (integrin alpha 9 beta 1)
    • Publication Date:
      Date Created: 20240318 Date Completed: 20240514 Latest Revision: 20241105
    • Publication Date:
      20241106
    • Accession Number:
      PMC11063402
    • Accession Number:
      10.1182/bloodadvances.2023012282
    • Accession Number:
      38498701