3 years ago

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

Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα
Paul W. Erhardt, Jun Qin, Jose Lopez, Liang Zhu, Dmitry A. Soloviev, Adam D. Munday, Can Shi, Valentin Ustinov, Kamila Bledzka, Yunmei Wang, Alexander Pavlovsky, Edward Plow, Huiyun Gao, Daniel I. Simon
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.

Publisher URL: http://www.nature.com/articles/ncomms15559

DOI: 10.1038/ncomms15559

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