PI3Kγ Mediates Microglial Proliferation and Cell Viability via ROS

(1) Background: Rapid microglial proliferation contributes to the complex responses of the innate immune system in the brain to various neuroinflammatory stimuli. Here, we investigated the regulatory function of phosphoinositide 3-kinase gamma (PI3K gamma) and reactive oxygen species (ROS) for rapid proliferation of murine microglia induced by LPS and ATP. (2) Methods: PI3K gamma knockout mice (PI3K gamma KO), mice expressing catalytically inactive PI3K gamma (PI3K gamma KD) and wild-type mice were assessed for microglial proliferation using an in vivo wound healing assay. Additionally, primary microglia derived from newborn wild-type, PI3K gamma KO and PI3K gamma KD mice were used to analyze PI3K gamma effects on proliferation and cell viability, senescence and cellular and mitochondrial ROS production; the consequences of ROS production for proliferation and cell viability after LPS or ATP stimulation were studied using genetic and pharmacologic approaches. (3) Results: Mice with a loss of lipid kinase activity showed impaired proliferation of microglia. The prerequisite of induced microglial proliferation and cell viability appeared to be PI3K gamma-mediated induction of ROS production. (4) Conclusions: The lipid kinase activity of PI3K gamma plays a crucial role for microglial proliferation and cell viability after acute inflammatory activation.

Automated summary

The lipid kinase activity of PI3K gamma is crucial for microglial proliferation and cell viability after acute inflammatory activation, with PI3K gamma-mediated induction of ROS production being a prerequisite for induced microglial proliferation and cell viability.