Leukocyte engagement of platelet glycoprotein Ib alpha via the integrin Mac-1 is critical for the biological response to vascular injury

Article

关键词: DECREASED NEOINTIMAL FORMATION;    P-SELECTIN;    INTIMAL HYPERPLASIA;    ADHERENT PLATELETS;    MICE REVEALS;    BINDING-SITE;    ADHESION;    CD11B/CD18;    NEUTROPHIL;    RECRUITMENT;   

DOI  :  10.1161/CIRCULATIONAHA.105.571315

来源: SCIE

【 摘 要 】

Background-Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (alpha(M)beta(2), CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise alpha(M)beta(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 alpha I-M domain as the binding site for platelet glycoprotein (GP) Ib alpha. Here we report that antibody targeting of alpha(M)(P-201-K-217) reduced alpha(M)beta(2)-dependent adhesion to GP Ib alpha but not other alpha M beta 2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-M-alpha(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 alpha(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 Ib alpha is a physiologically relevant ligand for alpha(M)beta(2) and that integrin engagement of GP Ib alpha 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.

【 授权许可】

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