Background— Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (α_Mβ₂, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise α_Mβ₂ 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 P²⁰¹-K²¹⁷ sequence in the α_MI domain as the binding site for platelet glycoprotein (GP) Ibα. Here we report that antibody targeting of α_M(P²⁰¹-K²¹⁷) reduced α_Mβ₂-dependent adhesion to GP Ibα but not other α_Mβ₂ ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-α_M(P²⁰¹-K²¹⁷) 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(P²⁰¹-K²¹⁷) 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_Mβ₂ 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.