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

Nat Commun. 2017 May 30;8:15559. doi: 10.1038/ncomms15559.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Bleeding Time
  • Blood Coagulation
  • Blood Platelets / cytology
  • Blood Platelets / immunology*
  • Blood Platelets / metabolism
  • Carotid Arteries / pathology
  • Glucosamine / chemistry
  • Hemostasis
  • Inflammation
  • Leukocytes / cytology
  • Leukocytes / metabolism*
  • Macrophage-1 Antigen / genetics*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microcirculation
  • NIH 3T3 Cells
  • Partial Thromboplastin Time
  • Phagocytosis
  • Platelet Activation
  • Platelet Count
  • Platelet Glycoprotein GPIb-IX Complex / metabolism*
  • Protein Binding
  • Protein Domains
  • Signal Transduction
  • Thrombin / metabolism
  • Thrombosis / immunology*

Substances

  • Macrophage-1 Antigen
  • Platelet Glycoprotein GPIb-IX Complex
  • adhesion receptor
  • Thrombin
  • Glucosamine