Abstract
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-3Kγ can be activated directly by the βγ 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-3Kγ in leukocyte arrest. PI-3Kγ null mice showed an 80% decrease in CXCL1-induced leukocyte adhesion in venules of the exteriorized mouse cremaster muscle. In wildtype mice, rolling leukocytes showed rapid and sustained adhesion, but in PI-3Kγ-/- mice, adhesion was not triggered at all or was transient, suggesting that absence of PI-3Kγ interferes with integrin bond strengthening. Wild-type mice reconstituted with PI-3Kγ null bone marrow showed a 50% decrease in CXCL1-induced leukocyte adhesion. In a blood-perfused micro-flow chamber, leukocytes from PI-3Kγ-/- mice showed a defect in adhesion on a P-selectin/ICAM-1/CXCL1 substrate, indicating that leukocyte PI-3Kγ was required for adhesion. The adhesion defect in PI-3Kγ-/- mice was as severe as that in mice lacking LFA-1, the major integrin responsible for neutrophil adhesion. We conclude that the γ isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation.
Original language | English (US) |
---|---|
Pages (from-to) | 1491-1499 |
Number of pages | 9 |
Journal | Journal of Leukocyte Biology |
Volume | 80 |
Issue number | 6 |
DOIs | |
State | Published - Dec 2006 |
Externally published | Yes |
Keywords
- Cell trafficking
- Inflammation
- Signal transduction
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Cell Biology