Kinase activity of phosphoinositide 3‐kinase gamma (PI3Kγ) is important for neutrophil infiltration in inflammation

Phosphoinositide 3‐kinase (PI3K) is a family of lipid kinases that generates phosphatidylinositol 3, 4, 5‐trisphosphate in the plasma membrane to recruit and activate downstream signaling molecules. PI3Kγ is the only member of the class IB subfamily and it is composed of a catalytic subunit p110γ and one of the two regulatory subunits, p101 or p84. PI3Kγ activation is driven by G‐protein coupled receptors responding to chemotactic ligands. In autoimmune diseases, neutrophils are one of the major cell types causing the pathological outcome and tissue damage. Infiltration of neutrophils to site of inflammation is mediated by a wide variety of chemotactic factors. To demonstrate the role of PI3Kγ in neutrophil migration in vivo , knock‐in mice with inactive PI3Kγ were tested in two acute local inflammation models, arachindonic acid‐induced dermal inflammation and chemokine (RANTES)‐induced peritoneal cellular influx. Neutrophil infiltration was significantly reduced in PI3Kγ inactive mice when compared to wild‐type control mice in both models. The results suggest that PI3Kγ kinase activity plays an important role in neutrophil migration. Thus, inhibition of PI3Kγ kinase activity with small molecules could represent a promising approach for the treatment of inflammation and autoimmune diseases.