Published online before print September 22, 2006
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is required for chemokine-induced, sustained adhesion under flow in vivo
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Departments of *Molecular Physiology and Biophysics and Biomedical Engineering, and Cardiovascular Research Center, University of Virginia, Charlottesville; and Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington
@ To whom correspondence should be addressed. E-mail: klausley{at}virginia.edu.
During inflammation, leukocytes roll along the wall of postcapillary venules scanning the surface for immobilized CXCL1, a chemokine that triggers firm adhesion by activating CXCR2 on the neutrophil. PI-3K are signaling molecules important in cellular processes, ranging from cellular differentiation to leukocyte migration. PI-3K
can be activated directly by the 
dimer of heterotrimeric G proteins coupled to CXCR2. Here, we used in vivo and ex vivo intravital microscopy models to test the role of PI-3K in leukocyte arrest. PI-3K null mice showed an 80% decrease in CXCL1-induced leukocyte adhesion in venules of the exteriorized mouse cremaster muscle. In wild-type mice, rolling leukocytes showed rapid and sustained adhesion, but in PI-3K-/- mice, adhesion was not triggered at all or was transient, suggesting that absence of PI-3K interferes with integrin bond strengthening. Wild-type mice reconstituted with PI-3K null bone marrow showed a 50% decrease in CXCL1-induced leukocyte adhesion. In a blood-perfused micro-flow chamber, leukocytes from PI-3K-/- mice showed a defect in adhesion on a P-selectin/ICAM-1/CXCL1 substrate, indicating that leukocyte PI-3K was required for adhesion. The adhesion defect in PI-3K-/- mice was as severe as that in mice lacking LFA-1, the major integrin responsible for neutrophil adhesion. We conclude that the isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation.
Key Words: signal transduction • cell trafficking • inflammation
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