Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation

TLDR

Phosphoinositide 3‑kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor‑activated isoforms are unclear. PI3Kγ‑deficient mice are viable but exhibit impaired neutrophil PIP3 production, AKT activation, respiratory burst, and motility, and macrophages show reduced chemotaxis and defective accumulation in septic peritonitis, demonstrating PI3Kγ’s essential role in macrophage recruitment during inflammation.

Abstract

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 PI3Kγ were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kγ −/− neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kγ-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 PI3Kγ is a crucial signaling molecule required for macrophage accumulation in inflammation.