Published Online
on October 31, 2005

A more recent version of this article appeared on November 8, 2005

This Article Full Text (PDF) All Versions of this Article: 112/19/2993    most recent CIRCULATIONAHA.105.571315v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Simon, D. I. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Simon, D. I. Related Collections Restenosis Animal models of human disease Cell biology/structural biology Platelets Mechanism of atherosclerosis/growth factors Other Vascular biology

Submitted on May 18, 2005
Revised on August 2, 2005
Accepted on August 22, 2005

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, and 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.).

^* To whom correspondence should be addressed. E-mail: dsimon{at}rics.bwh.harvard.edu.

Background--Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (_M2, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise _M2 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 _M2-dependent adhesion to GP Ib but not other _M2 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 _M2 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.

Key words: cell adhesion molecules • inflammation • leukocytes • platelets • restenosis

This article has been cited by other articles:

				J. Hirahashi, K. Hishikawa, S. Kaname, N. Tsuboi, Y. Wang, D. I. Simon, G. Stavrakis, T. Shimosawa, L. Xiao, Y. Nagahama, et al. Mac-1 (CD11b/CD18) Links Inflammation and Thrombosis After Glomerular Injury Circulation, September 29, 2009; 120(13): 1255 - 1265. [Abstract] [Full Text] [PDF]

				K. Croce, H. Gao, Y. Wang, T. Mooroka, M. Sakuma, C. Shi, G. K. Sukhova, R. R.S. Packard, N. Hogg, P. Libby, et al. Myeloid-Related Protein-8/14 Is Critical for the Biological Response to Vascular Injury Circulation, August 4, 2009; 120(5): 427 - 436. [Abstract] [Full Text] [PDF]

				M. T. Yiming, D. J. Lederer, L. Sun, A. Huertas, A. C. Issekutz, and S. Bhattacharya Platelets Enhance Endothelial Adhesiveness in High Tidal Volume Ventilation Am. J. Respir. Cell Mol. Biol., November 1, 2008; 39(5): 569 - 575. [Abstract] [Full Text] [PDF]

				E. Pluskota, N. M. Woody, D. Szpak, C. M. Ballantyne, D. A. Soloviev, D. I. Simon, and E. F. Plow Expression, activation, and function of integrin {alpha}M{beta}2 (Mac-1) on neutrophil-derived microparticles Blood, September 15, 2008; 112(6): 2327 - 2335. [Abstract] [Full Text] [PDF]

				G. Li, J. M. Sanders, M. H. Bevard, Z. Sun, J. W. Chumley, E. V. Galkina, K. Ley, and I. J. Sarembock CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury Am. J. Pathol., April 1, 2008; 172(4): 1141 - 1152. [Abstract] [Full Text] [PDF]

				M. K. Crow Collaboration, Genetic Associations, and Lupus Erythematosus N. Engl. J. Med., February 28, 2008; 358(9): 956 - 961. [Full Text] [PDF]

				S. Jain, M. Zuka, J. Liu, S. Russell, J. Dent, J. A. Guerrero, J. Forsyth, B. Maruszak, T. K. Gartner, B. Felding-Habermann, et al. Platelet glycoprotein Ib{alpha} supports experimental lung metastasis PNAS, May 22, 2007; 104(21): 9024 - 9028. [Abstract] [Full Text] [PDF]

				M. Sircar, P. F. Bradfield, M. Aurrand-Lions, R. J. Fish, P. Alcaide, L. Yang, G. Newton, D. Lamont, S. Sehrawat, T. Mayadas, et al. Neutrophil Transmigration under Shear Flow Conditions In Vitro Is Junctional Adhesion Molecule-C Independent J. Immunol., May 1, 2007; 178(9): 5879 - 5887. [Abstract] [Full Text] [PDF]

				S. U. Eisenhardt, M. Schwarz, N. Schallner, J. Soosairajah, N. Bassler, D. Huang, C. Bode, and K. Peter Generation of activation-specific human anti-{alpha}M{beta}2 single-chain antibodies as potential diagnostic tools and therapeutic agents Blood, April 15, 2007; 109(8): 3521 - 3528. [Abstract] [Full Text] [PDF]

				M. Osaka, S. Hagita, M. Haraguchi, M. Kajimura, M. Suematsu, and M. Yoshida Real-time imaging of mechanically injured femoral artery in mice reveals a biphasic pattern of leukocyte accumulation Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1876 - H1882. [Abstract] [Full Text] [PDF]

				W. Bergmeier, C. L. Piffath, T. Goerge, S. M. Cifuni, Z. M. Ruggeri, J. Ware, and D. D. Wagner The role of platelet adhesion receptor GPIb{alpha} far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis PNAS, November 7, 2006; 103(45): 16900 - 16905. [Abstract] [Full Text] [PDF]

				Z. Li, A. R. Burns, and C. W. Smith Lymphocyte Function-Associated Antigen-1-Dependent Inhibition of Corneal Wound Healing Am. J. Pathol., November 1, 2006; 169(5): 1590 - 1600. [Abstract] [Full Text] [PDF]

				E. Harokopakis, M. H. Albzreh, M. H. Martin, and G. Hajishengallis TLR2 Transmodulates Monocyte Adhesion and Transmigration via Rac1- and PI3K-Mediated Inside-Out Signaling in Response to Porphyromonas gingivalis Fimbriae. J. Immunol., June 15, 2006; 176(12): 7645 - 7656. [Abstract] [Full Text] [PDF]

				E. Galkina and K. Ley Double Jeopardy: How Soluble P-Selectin Activates Leukocytes in Peripheral Arterial Occlusive Disease Circ. Res., January 6, 2006; 98(1): 12 - 14. [Full Text] [PDF]