Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3-Kinase Isoforms for Neutrophil Recruitment Induced by Chemoattractants in Vivo

PI3K plays a fundamental role in regulating neutrophil recruitment into sites of inflammation but the role of the different isoforms of PI3K remains unclear. In this study, we evaluated the role of PI3Kγ and PI3Kδ for neutrophil influx induced by the exogenous administration or the endogenous generation of the chemokine CXCL1. Administration of CXCL1 in PI3Kγ−/− or wild-type (WT) mice induced similar increases in leukocyte rolling, adhesion, and emigration in the cremaster muscle when examined by intravital microscopy. The induction of neutrophil recruitment into the pleural cavity or the tibia-femoral joint induced by the injection of CXCL1 was not significantly different in PI3Kγ−/− or WT mice. Neutrophil influx was not altered by treatment of WT mice with a specific PI3Kδ inhibitor, IC87114, or a specific PI3Kγ inhibitor, AS605240. The administration of IC87114 prevented CXCL1-induced neutrophil recruitment only in presence of the PI3Kγ inhibitor or in PI3Kγ−/− mice. Ag challenge of immunized mice induced CXCR2-dependent neutrophil recruitment that was inhibited by wortmannin or by blockade of and PI3Kδ in PI3Kγ−/− mice. Neutrophil recruitment to bronchoalveolar lavage induced by exogenously added or endogenous production of CXCL1 was prevented in PI3Kγ−/− mice. The accumulation of the neutrophils in lung tissues was significantly inhibited only in PI3Kγ−/− mice treated with IC87114. Neutrophil recruitment induced by exogenous administration of C5a or fMLP appeared to rely solely on PI3Kγ. Altogether, our data demonstrate that there is a tissue- and stimulus-dependent role of PI3Kγ and PI3Kδ for neutrophil recruitment induced by different chemoattractants in vivo.