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

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 and Daniel I. Simon ()
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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
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

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15559

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