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

Abstract

Background— Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (α M β 2 , CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise α M β 2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified. Methods and Results— Our previous studies have established the P 201 -K 217 sequence in the α M I domain as the binding site for platelet glycoprotein (GP) Ibα. Here we report that antibody targeting of α M (P 201 -K 217 ) reduced α M β 2 -dependent adhesion to GP Ibα but not other α M β 2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-α M (P 201 -K 217 ) inhibited the firm adhesion of both human and murine leukocytes to adherent platelets under laminar flow conditions. In a mouse femoral artery wire injury model, antibody targeting of α M (P 201 -K 217 ) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening. Conclusions— This study demonstrates that GP Ibα is a physiologically relevant ligand for α M β 2 and that integrin engagement of GP Ibα 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.