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

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.

Platelets stimulated by IgG-coated surfaces bind and activate neutrophils through a selectin-dependent pathway

“…The selectin mediated tethering and rolling mechanisms of neutrophils and platelets are highly shear dependent. Leukocyte  2 -integrins may bind directly to ICAM-2, via fibrinogen bridging indirectly to GpIIb/IIIa (CD41/CD61 or IIb/IIIa) [14] or possibly to GpIb [15]. It is generally considered that an integrin-mediated firm adhesion of neutrophils to endothelial cells or platelets require a prior selectin-dependent interaction.…”

Involvement of platelet glycoprotein Ib in platelet microparticle mediated neutrophil activation

“…CD11b/ 18). Further adhesion partners of Mac-1 on the activated platelet cell membrane are GPIb [8] and Jam-3 [34]. Recently, Simon and his colleagues further identified aMI domain of Mac-1 as the binding site for platelet glycoprotein Iba and established the crucial role of GPIb-Mac-1 engagement for the biological response in vascular injury [35].…”

“…The epitope mapping may explain for their different bridging effectiveness. AP1 binds to the outside COOH-terminal flanking and leucine-rich repeat region of GPIb (amino acid 201-268), while SZ2 maps to the sulfated tyrosine residues encompassing amino acids 268-282, which is nearer to the platelet membrane [8,45]. However, the exact mode of action needs further investigation.…”

“…During the inflammation process, the interaction of neutrophils with activated platelets is coordinated by an adhesion cascade [7] in which platelet P-selectin binds to P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes to promote the initial tethering of the cells and the subsequent firm adhesion is mediated by b2 integrin CD11b/ 18 (Mac-1) binding to either platelet-GPIb [8] or to fibrinogen bound to platelet GPIIb/IIIa or integrin avb3 [9].…”

“…Recently, Simon et al reported that platelet GPIba is the counter-receptor for Mac-1 on leukocyte, accounting for firm adhesion and trans-platelet migration of leukocytes on vascular thrombus [8]. It has been previously reported that platelet MP expressed less P-selectin than platelet and the interaction between platelet MP and neutrophil is somehow different from plateletneutrophil interaction with regard to P-selectin and sialyl Lewis inhibitory studies [21].…”