Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIb?.

ABSTRACT: Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin ?M?2, or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIb? 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 GPIb? 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:GPIb? inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIb?, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC5477519 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature