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Leukocyte phosphoinositide‐3 kinase γ is required for chemokine‐induced, sustained adhesion under flow in vivo
Author(s) -
Smith David F.,
Deem Tracy L.,
Bruce Anthony C.,
Reutershan Jörg,
Wu Daniel,
Ley Klaus
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0306227
Subject(s) - intravital microscopy , cxcl1 , microbiology and biotechnology , biology , cxc chemokine receptors , integrin , chemokine , cell adhesion molecule , ex vivo , adhesion , in vivo , immunology , inflammation , chemistry , chemokine receptor , biochemistry , receptor , organic chemistry
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 wild‐type 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.