Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo

David F. Smith, Tracy L. Deem, Anthony C. Bruce, Jörg Reutershan, Daniel Wu, Klaus Ley

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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 languageEnglish (US)
Pages (from-to)1491-1499
Number of pages9
JournalJournal of Leukocyte Biology
Volume80
Issue number6
DOIs
StatePublished - Dec 2006
Externally publishedYes

Keywords

  • Cell trafficking
  • Inflammation
  • Signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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