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Blood, 1 July 2005, Vol. 106, No. 1, pp. 150-157.
Prepublished online as a Blood First Edition Paper on March 15, 2005; DOI 10.1182/blood-2005-01-0023.
 Previous Article | Next Article 
Submitted January 5, 2005
Accepted February 14, 2005
The role of endothelial PI3K activity in neutrophil trafficking
Kamal D Puri, Teresa A Doggett, Ching-Yu Huang, Jason Douangpanya, Joel S Hayflick, Martin Turner, Josef Penninger, and Thomas G Diacovo*
ICOS Corporation, Bothell, WA, USA
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
* Corresponding author; email: diacovo_t{at}kids.wustl.edu.
Phosphoinositide 3-kinase gamma (PI3K ) activity 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 PI3K 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 p110-/- 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 p110-/- microvessels in vivo in response to TNF . This alteration in adhesion was further augmented by a deficiency in p110 , 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 p110-/- mice was impaired by > 95%, but no defect in NF- B-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.
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