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(Circulation. 2005;112:2993-3000.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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

Yunmei Wang, PhD^*; Masashi Sakuma, MD^*; Zhiping Chen, MS^*; Valentin Ustinov, PhD; Can Shi, PhD; Kevin Croce, MD, PhD; Alexandre C. Zago, MD; Jose Lopez, MD; Patrick Andre, PhD; Edward Plow, PhD; Daniel I. Simon, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (Y.W., M.S., Z.C., C.S., K.C., A.C.Z., D.I.S.); The Cleveland Clinic Foundation, Cleveland, Ohio (V.U., E.P.); Thrombosis Research Section, Departments of Medicine and Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex (J.L.); and Portola Pharmaceuticals, South San Francisco, Calif (P.A.).

Correspondence to Daniel I. Simon, MD, Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. E-mail dsimon{at}rics.bwh.harvard.edu

Received May 18, 2005; de novo received June 24, 2005; revision received August 2, 2005; accepted August 22, 2005.

Background— Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (_Mß₂, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise _Mß₂ 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 _MI domain as the binding site for platelet glycoprotein (GP) Ib. Here we report that antibody targeting of _M(P²⁰¹-K²¹⁷) reduced _Mß₂-dependent adhesion to GP Ib but not other _Mß₂ ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-_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 _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 Ib is a physiologically relevant ligand for _Mß₂ and that integrin engagement of GP Ib 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.

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