Abstract
(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 γ (PI3Kγ) and reactive oxygen species (ROS) for rapid proliferation of murine microglia induced by LPS and ATP. (2) Methods: PI3Kγ knockout mice (PI3Kγ KO), mice expressing catalytically inactive PI3Kγ (PI3Kγ 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, PI3Kγ KO and PI3Kγ KD mice were used to analyze PI3Kγ 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 PI3Kγ-mediated induction of ROS production. (4) Conclusions: The lipid kinase activity of PI3Kγ plays a crucial role for microglial proliferation and cell viability after acute inflammatory activation.
Highlights
Microglia, the self-renewing innate immune cells of the central nervous system (CNS), are the resident macrophages of the CNS
Insults or infections affecting the CNS are accompanied by a series of parenchymal events including release of damage-associated molecular pattern molecules (DAMPs) from impaired tissue or invasion of pathogen molecular pattern molecules (PAMPs) such as lipopolysaccharide (LPS), which results in activation of microglia and their increased motility and phagocytic activities [1,9,10]
By using genetic and pharmacologic approaches, we demonstrate that both DAMP adenosine triphosphate (ATP) and the prototypical PAMP LPS activate microglial proliferation and cell viability in a phosphoinositide 3-kinase γ (PI3Kγ)-dependent manner
Summary
The self-renewing innate immune cells of the central nervous system (CNS), are the resident macrophages of the CNS. They are the key mediators of the innate immune response [1,2]. They control the neuronal patterning and wiring of the brain in early development and fulfill supportive functions for maintenance of tissue homeostasis, tissue support, neuroplasticity and neuroprotection due to their ability to surveil the microenvironment for alterations [3,4,5,6]. Insults or infections affecting the CNS are accompanied by a series of parenchymal events including release of damage-associated molecular pattern molecules (DAMPs) from impaired tissue or invasion of pathogen molecular pattern molecules (PAMPs) such as lipopolysaccharide (LPS), which results in activation of microglia and their increased motility and phagocytic activities [1,9,10].
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