Leukocyte PI3Kgamma and PI3Kdelta have temporally distinct roles for leukocyte recruitment in vivo.

Phosphoinositide 3-kinases (PI3Ks) have been considered important in leukocyte motility. PI3Kgamma, the class I(B) PI3K, expressed prominently in leukocytes and also in endothelial cells, mediates leukocyte functional responses induced by chemoattractants. To reveal its role in leukocyte recruitment, we used intravital microscopy to directly visualize leukocyte rolling, adhesion, and emigration in postcapillary venules in PI3Kgamma-deficient (PI3Kgamma(-/-)) mice. We report here that PI3Kgamma deficiency had no significant effects on leukocyte rolling flux or rolling velocity and minor effects on adhesion (30% to 35%) in response to CXC chemokine MIP-2 (CXCL2) or KC (CXCL1). However, leukocyte emigration was severely impaired in PI3Kgamma(-/-) mice in an early (first 90 minutes) response to MIP-2 or KC. Chimeric mice receiving bone marrow transplants revealed that this early response was entirely dependent upon PI3Kgamma in neutrophils but not parenchymal cells (endothelium and others). Identical responses were observed when endogenous chemokine production was induced by TNFalpha; leukocyte emigration was reduced in PI3Kgamma(-/-) mice. More prolonged responses to MIP-2 (for 4 to 5 hours) or TNFalpha (6 to 8 hours) were almost entirely PI3Kgamma independent and largely dependent on PI3Kdelta. Our results reveal that leukocyte emigration response to CXC chemokines is entirely dependent upon PI3Kgamma or PI3Kdelta, but these are nonoverlapping, temporally distinct events in inflamed tissues in vivo.