Platelet Glycoprotein Ibα Is a Counterreceptor for the Leukocyte Integrin Mac-1 (Cd11b/Cd18)

TLDR

Leukocyte firm adhesion and transplatelet migration on vascular thrombus require the interaction between the leukocyte integrin Mac‑1 and a platelet counterreceptor that had not yet been identified. The study aimed to identify that counterreceptor as platelet glycoprotein Ibα, a component of the GP Ib‑IX‑V complex. Experiments showed that Mac‑1 binds GP‑Ibα through its I domain and the receptor’s leucine‑rich repeat and C‑terminal regions, mediating leukocyte adhesion and rolling under flow and indicating GP‑Ibα as a therapeutic target to disrupt leukocyte‑platelet complexes in vascular inflammation.

Abstract

The firm adhesion and transplatelet migration of leukocytes on vascular thrombus are both dependent on the interaction of the leukocyte integrin, Mac-1, and a heretofore unknown platelet counterreceptor. Here, we identify the platelet counterreceptor as glycoprotein (GP) Ibα, a component of the GP Ib-IX-V complex, the platelet von Willebrand factor (vWf) receptor. THP-1 monocytic cells and transfected cells that express Mac-1 adhered to GP Ibα–coated wells. Inhibition studies with monoclonal antibodies or receptor ligands showed that the interaction involves the Mac-1 I domain (homologous to the vWf A1 domain), and the GP Ibα leucine-rich repeat and COOH-terminal flanking regions. The specificity of the interaction was confirmed by the finding that neutrophils from wild-type mice, but not from Mac-1–deficient mice, bound to purified GP Ibα and to adherent platelets, the latter adhesion being inhibited by pretreatment of the platelets with mocarhagin, a protease that specifically cleaves GP Ibα. Finally, immobilized GP Ibα supported the rolling and firm adhesion of THP-1 cells under conditions of flow. These observations provide a molecular target for disrupting leukocyte–platelet complexes that promote vascular inflammation in thrombosis, atherosclerosis, and angioplasty-related restenosis.