The Role of Endothelial PI3Kγ Activity in Neutrophil Trafficking.

Phosphoinositide 3-kinase gamma (PI3Kγ) in neutrophils plays a critical role in the directed-migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3Kγ activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class Ib PI3K function in neutrophils of p110γ^−/− mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in WT neutrophil attachment to and 17-fold increase in rolling velocities on p110γ^−/− microvessels in vivo in response to TNFα. This alteration in adhesion was further augmented by a deficiency in p110δ, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin-mediated adhesion in p110gamma]^−/− mice was impaired by > 95%, but no defect in NF-κB-induced gene expression was observed. These findings suggest a previously unrecognized partnership between class I PI3Ks expressed in leukocytes and endothelium, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation.