Promotion of Leukocyte Adhesion by a Novel Interaction Between Vitronectin and the β2 Integrin Mac-1 (αMβ2, CD11b/CD18)

Objective—The leukocyte integrin Mac-1 (αMβ2, CD11b/CD18) binds a number of ligands and counter-receptors and thereby is a major determinant in regulation of leukocyte adhesion and extravasation. Vitronectin (VN) is an adhesion-promoting factor that is abundantly present as matrix molecule in vascular diseases such as atherosclerosis. Until now, only an indirect interaction between Mac-1 and VN via the urokinase receptor (urokinase plasminogen activator receptor) was known. We now propose that Mac-1 and VN can directly interact with each other. Methods and Results—In an in vitro system with purified components, Mac-1 specifically bound the multimeric matrix form of VN but not the monomeric plasma form. Using various competitors, the interaction domains in Mac-1 and VN were localized. Mac-1–expressing but not untransfected Chinese hamster ovary cells adhered strongly on VN. Introduction of a GFFKR deletion in the αM subunit of Mac-1, which increases the constitutive activation of the integrin, led to increased adhesion on VN. Peripheral human blood neutrophils adhered and migrated on multimeric VN in a Mac-1–dependent manner. Conclusions—These results show that there is a specific integrin-affinity–regulated interaction between Mac-1 and the matrix form but not the plasma form of VN that may significantly participate in leukocyte adhesion and extravasation.

[1]  K. Preissner,et al.  Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1 , 2003, Journal of Cell Science.

[2]  D. Lawrence,et al.  Sequences within Domain II of the Urokinase Receptor Critical for Differential Ligand Recognition* , 2003, Journal of Biological Chemistry.

[3]  R. Read,et al.  How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration , 2003, Nature Structural Biology.

[4]  E. Plow,et al.  Convergence of the adhesive and fibrinolytic systems: recognition of urokinase by integrin alpha Mbeta 2 as well as by the urokinase receptor regulates cell adhesion and migration. , 2003, Blood.

[5]  T. Ugarova,et al.  The interplay between integrins αmβ2 and α5β1 during cell migration to fibronectin , 2003 .

[6]  M. Olschewski,et al.  Adhesion of Monocytes to Medical Steel as Used for Vascular Stents is Mediated by the Integrin Receptor Mac-1 (CD11b/CD18; α M β 2 ) and Can be Inhibited by Semiconductor Coating , 2003, Cell communication & adhesion.

[7]  H. Petty,et al.  Function of the Lectin Domain of Mac-1/Complement Receptor Type 3 (CD11b/CD18) in Regulating Neutrophil Adhesion1 , 2002, The Journal of Immunology.

[8]  P. Carmeliet,et al.  Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[9]  K. Preissner,et al.  Urokinase receptor surface expression regulates monocyte adhesion in acute myocardial infarction. , 2002, Blood.

[10]  M. A. Arnaout,et al.  Integrin structure: new twists and turns in dynamic cell adhesion , 2002, Immunological reviews.

[11]  J. Bonnet,et al.  Vitronectin is up-regulated after vascular injury and vitronectin blockade prevents neointima formation. , 2002, Cardiovascular research.

[12]  R. Colman,et al.  Regulation of leukocyte recruitment by polypeptides derived from high molecular weight kininogen , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  R. Czekay,et al.  Plasminogen activator inhibitor‐1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin , 2001, Journal of cellular physiology.

[14]  N. Hogg,et al.  Shape and shift changes related to the function of leukocyte integrins LFA‐1 and Mac‐1 , 2001, Journal of leukocyte biology.

[15]  T. Ugarova,et al.  Recognition of Fibrinogen by Leukocyte Integrins , 2001, Annals of the New York Academy of Sciences.

[16]  M. Sixt,et al.  Cell Adhesion and Migration Properties of β2-Integrin Negative Polymorphonuclear Granulocytes on Defined Extracellular Matrix Molecules , 2001, The Journal of Biological Chemistry.

[17]  G. Zimmerman,et al.  The Leukocyte Integrins* , 2000, The Journal of Biological Chemistry.

[18]  K. Dib,et al.  BETA 2 integrin signaling in leukocytes. , 2000, Frontiers in bioscience : a journal and virtual library.

[19]  M. Ehlers,et al.  CR3: a general purpose adhesion-recognition receptor essential for innate immunity. , 2000, Microbes and infection.

[20]  E. Edelman,et al.  Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. , 2000, The Journal of clinical investigation.

[21]  C. Bode,et al.  Heparin inhibits ligand binding to the leukocyte integrin Mac-1 (CD11b/CD18). , 1999, Circulation.

[22]  P. Gaehtgens,et al.  Impairment of neutrophil emigration in CD18-null mice. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[23]  K. Preissner,et al.  Urokinase Receptor (CD87) Regulates Leukocyte Recruitment via β2 Integrins In Vivo , 1998, The Journal of experimental medicine.

[24]  J. Bonnet,et al.  Vitronectin expression and interaction with receptors in smooth muscle cells from human atheromatous plaque. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[25]  K. Preissner,et al.  Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. , 1997, Experimental cell research.

[26]  Timothy A. Springer,et al.  Folding of the N-terminal, ligand-binding region of integrin α-subunits into a β-propeller domain , 1997 .

[27]  O. Majdic,et al.  Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. , 1996, Blood.

[28]  M. Raida,et al.  Structural and functional characterization of vitronectin-derived RGD-containing peptides from human hemofiltrate. , 1996, European journal of biochemistry.

[29]  Michael V. Doyle,et al.  Regulation of Integrin Function by the Urokinase Receptor , 1996, Science.

[30]  K. Preissner,et al.  The urokinase receptor is a major vitronectin-binding protein on endothelial cells. , 1996, Experimental cell research.

[31]  M. Gyetko,et al.  The urokinase receptor (CD87) facilitates CD11b/CD18-mediated adhesion of human monocytes. , 1996, The Journal of clinical investigation.

[32]  R. Pardi,et al.  Conserved regions in the cytoplasmic domains of the leukocyte integrin alpha L beta 2 are involved in endoplasmic reticulum retention, dimerization, and cytoskeletal association. , 1995, Journal of immunology.

[33]  T. O’Toole,et al.  Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction , 1995, The Journal of experimental medicine.

[34]  V. Holers,et al.  Complement receptor 3 (CR3, Mac-1, integrin alpha M beta 2, CD11b/CD18) is required for tyrosine phosphorylation of paxillin in adherent and nonadherent neutrophils , 1994, Journal of Cell Biology.

[35]  R. Clark,et al.  Wound repair in the context of extracellular matrix. , 1994, Current opinion in cell biology.

[36]  D. Waltz,et al.  Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. , 1994, The Journal of biological chemistry.

[37]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[38]  R. Timpl,et al.  Multimeric vitronectin. Identification and characterization of conformation-dependent self-association of the adhesive protein. , 1993, The Journal of biological chemistry.

[39]  D. Altieri,et al.  Occupancy of CD11b/CD18 (Mac-1) divalent ion binding site(s) induces leukocyte adhesion. , 1991, Journal of immunology.

[40]  G. Zimmerman,et al.  Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. , 2002, Current opinion in hematology.

[41]  G. D. Ross,et al.  Regulation of the adhesion versus cytotoxic functions of the Mac-1/CR3/alphaMbeta2-integrin glycoprotein. , 2000, Critical reviews in immunology.

[42]  Zhangli.  The αMβ2 integrin and its role in neutrophil function , 1999 .

[43]  T. Springer.  Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  C. Bode,et al.  A deletion in the alpha subunit locks platelet integrin alpha IIb beta 3 into a high affinity state. , 1996, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.