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Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα

Author

Listed:
  • Yunmei Wang

    (Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center)

  • Huiyun Gao

    (Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center)

  • Can Shi

    (Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center)

  • Paul W. Erhardt

    (University of Toledo College of Pharmacy and Pharmaceutical Sciences)

  • Alexander Pavlovsky

    (University of Toledo College of Pharmacy and Pharmaceutical Sciences)

  • Dmitry A. Soloviev

    (Cleveland Clinic)

  • Kamila Bledzka

    (Cleveland Clinic)

  • Valentin Ustinov

    (Cleveland Clinic
    Present address: Federal State Scientific Institute, Federal Research Centre Coal and Coal Chemistry, Siberian Branch of the Russian Academy of Sciences, Institute of Human Ecology, 650065 Kemerovo, Russia)

  • Liang Zhu

    (Cleveland Clinic)

  • Jun Qin

    (Cleveland Clinic)

  • Adam D. Munday

    (Bloodworks Northwest Research Institute)

  • Jose Lopez

    (Bloodworks Northwest Research Institute)

  • Edward Plow

    (Cleveland Clinic)

  • Daniel I. Simon

    (Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center)

Abstract

Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin αMβ2, or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIbα is required for injury responses in diverse disease models. However, the role of Mac-1 in thrombosis is undefined. Here we report that mice with Mac-1 deficiency (Mac-1−/−) or mutation of the Mac-1-binding site for GPIbα have delayed thrombosis after carotid artery and cremaster microvascular injury without affecting parameters of haemostasis. Adoptive wild-type leukocyte transfer rescues the thrombosis defect in Mac-1−/− mice, and Mac-1-dependent regulation of the transcription factor Foxp1 contributes to thrombosis as evidenced by delayed thrombosis in mice with monocyte-/macrophage-specific overexpression of Foxp1. Antibody and small-molecule targeting of Mac-1:GPIbα inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIbα, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk.

Suggested Citation

  • Yunmei Wang & Huiyun Gao & Can Shi & Paul W. Erhardt & Alexander Pavlovsky & Dmitry A. Soloviev & Kamila Bledzka & Valentin Ustinov & Liang Zhu & Jun Qin & Adam D. Munday & Jose Lopez & Edward Plow & , 2017. "Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15559
    DOI: 10.1038/ncomms15559
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