Stable adhesion and migration of human neutrophils requires phospholipase D-mediated activation of the integrin CD11b/CD18.

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Abstract

The pathways regulating integrin-mediated adhesion during neutrophil migration are incompletely defined. Using a flow-based model in which human neutrophils rolling on P-selectin were activated to migrate by the chemoattractant peptide fMLP, we investigated the role of phospholipase D (PLD). fMLP-stimulated PLD generation of phosphatidate (PtdOH); while inhibition of PtdOH production with butan-1-ol had no effect on the initial immobilisation of rolling neutrophils (supported by activation of constitutively surface-expressed beta(2)-integrin CD11b/CD18) it impaired longer-term stability of adhesion and reduced the rate of migration (supported by activation of de novo-exocytosed CD11b/CD18). PtdOH regulated these processes by controlling activation of exocytosed CD11b/CD18, and appeared to act by directly stimulating phosphatidylinositol 4-phosphate 5-kinase type I to generate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Cell-permeable PtdIns(4,5)P(2) recovered migration of neutrophils after PLD inhibition; PtdIns(4,5)P(2) appeared to act by promoting talin binding to CD18 and hence activating CD11b/CD18, as migration was inhibited when neutrophils were loaded with peptides previously shown to block the interaction between PtdIns(4,5)P(2) and talin or talin and CD18. Thus, these data indicate that PLD-synthesised PtdOH stimulates the generation of PtdIns(4,5)P(2), which in turn mediates talin binding to, and activation of, CD11b/CD18 required for neutrophil stable adhesion and migration.

Details

Original languageEnglish
Pages (from-to)3211-21
Number of pages11
JournalMolecular immunology
Volume44
Issue number12
Publication statusPublished - 1 May 2007

Keywords

  • migration, integrin, phospholipase D, phosphatidate, alcohol, phosphatidylinositol 4,5-bisphosphate, CD11b/CD18, adhesion