Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury.
BACKGROUND
Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise alphaMbeta2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified.


RESULTS
Our previous studies have established the P201-K217 sequence in the alphaMI domain as the binding site for platelet glycoprotein (GP) Ibalpha. Here we report that antibody targeting of alphaM(P201-K217) reduced alphaMbeta2-dependent adhesion to GP Ibalpha but not other alphaMbeta2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-alphaM(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 alphaM(P201-K217) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening.


CONCLUSIONS
This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha 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.
Wang
Yunmei
Y
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sakuma
Masashi
M
Chen
Zhiping
Z
Ustinov
Valentin
V
Shi
Can
C
Croce
Kevin
K
Zago
Alexandre C
AC
Lopez
Jose
J
Andre
Patrick
P
Plow
Edward
E
Simon
Daniel I
DI
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D002450:Cell Communication; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014652:Vascular Diseases / Q000097:blood*
D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1