Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation

Phosphoinositide 3-kinase (PI3K) activity is crucial for Leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice Lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3K gamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3K gamma(-/-) neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3K gamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3K gamma is a crucial signaling molecule required for macrophage accumulation in inflammation.