The role of endothelial PI3Kgamma activity in neutrophil trafficking.
Phosphoinositide 3-kinase gamma (PI3Kgamma) 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 PI3Kgamma 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 p110gamma-/- 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 wild-type (WT) neutrophil attachment to and 17-fold increase in rolling velocities on p110gamma-/- microvessels in vivo in response to tumor necrosis factor alpha (TNFalpha). This alteration in adhesion was further augmented by a deficiency in p110delta, 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 more than 95%, but no defect in nuclear factor kappa B (NF-kappaB)-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.
Puri
Kamal D
KD
ICOS Corporation, Bothell, WA, USA.
Doggett
Teresa A
TA
Huang
Ching-Yu
CY
Douangpanya
Jason
J
Hayflick
Joel S
JS
Turner
Martin
M
Penninger
Josef
J
Diacovo
Thomas G
TG
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002678:Chimera; D058544:Class Ib Phosphatidylinositol 3-Kinase; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D036904:Leukocyte Rolling / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D011247:Pregnancy
D019040:E-Selectin; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse