Leukocyte Engagement of Platelet Glycoprotein Ibα via the Integrin Mac-1 Is Critical for the Biological Response to Vascular Injury

Abstract

This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…Platelet-derived ICAM-2 mediates lymphocyte-platelet adhesion via CD11a/CD18; and ICAM-2 may also contribute to neutrophil rolling and firm arrest, mediated by CD11b/CD18 under flow conditions (Kuijper et al, 1998). Glycoprotein-Iba (GPIba) has also been identified as a ligand for CD11b/CD18 (Simon et al, 2000), and leukocyte engagement of platelet GPIba via CD11b/CD18 has been shown to be critical for leukocyte accumulation in a mouse femoral artery injury model (Wang et al, 2005).…”

Importância da interação entre a integrina Mac-1 dos leucócitos e a glicoproteína Iba das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular

“…20 recently reported that M 2 integrin can also bind to JAM-3 of platelets, cooperating with GPIb for the adhesion between neutrophils and platelets in vitro 20 . However, it was demonstrated in a previous study that anti-M2 had a minimal inhibitory effect (13% of inhibition) in the interaction between the receptors M 2 and JAM-3 10 .…”

“…The relative specificity of the inhibitory action of anti-M2 in relation to GPIb , that is, it does not react with ICAM-1, fibrinogen and JAM-3, suggests a small contribution of other ligands for M 2 integrin in the context of vascular injury, with stripped endothelium and platelet deposition 10 .…”

“…10 , using the M2 peptide, demonstrated that leukocyte recruitment by platelets is largely mediated by the interaction between Mac-1 integrin ( M 2 ) of the leucocytes and GPIb of the platelets, in humans as well as in mice, as the biological model is very similar and the percentage of inhibition resulting from adhesion studies were statistically significant and comparable (80% in humans and 70% in mice). Even under flow conditions, the results of the adhesion inhibition were also statistically significant and similar (92% in humans and 81% in mice) 10 In the present study, the data of the vascular injury experiment in mice allow us to conclude that leukocyte recruitment, after the vascular injury, depends on the interaction between Mac-1 integrin and GPIb , as a specific antibody (anti-M2 or M2 peptide) directed at blocking the P 201 -K 217 segment of the I M domain, which is responsible for the interaction of leukocyte Mac-1 integrin and platelet GPIb , promoted a statistically significant reduction of 75% in the leukocyte accumulation in the medial layer of the vessel, on the first day post-injury and reduced by 42% and 58% the leukocyte accumulation in the intimal layer of the vessel, 5 and 28 days after the vascular injury, respectively.…”

“…9 recently located the binding site of integrin Mac-1 of the leukocytes with the Ib glycoprotein (GP) of platelets inside the segment M In vitro studies with the M2 peptide showed a significant adhesion reduction of 293 cells, which express integrin Mac-1, to sGPIb , as well as a significant reduction of human leukocyte adhesion to platelets under continuous flow 10 .…”