PI3Kγ Mediates Microglial Proliferation and Cell Viability via ROS

GND
1101494891
Affiliation
Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany; caroline.schmidt1983@gmail.com (C.S.); nadschneble@freenet.de (N.S.-L.); joerg.mueller@med.uni-jena.de (J.P.M.)
Schmidt, Caroline;
GND
1084138549
Affiliation
Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany; caroline.schmidt1983@gmail.com (C.S.); nadschneble@freenet.de (N.S.-L.); joerg.mueller@med.uni-jena.de (J.P.M.)
Schneble-Löhnert, Nadine;
GND
1184939764
ORCID
0000-0002-2584-589X
Affiliation
Department of Neonatology, Heidelberg University Children’s Hospital, 69120 Heidelberg, Germany; Trim.Lajqi@med.uni-heidelberg.de
Lajqi, Trim;
GND
1178449637
Affiliation
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; REINHARD.WETZKER@med.uni-jena.de
Wetzker, Reinhard;
GND
1204861196
Affiliation
Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany; caroline.schmidt1983@gmail.com (C.S.); nadschneble@freenet.de (N.S.-L.); joerg.mueller@med.uni-jena.de (J.P.M.)
Müller, Jörg P.;
GND
120228920
ORCID
0000-0002-4294-3758
Affiliation
Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany; caroline.schmidt1983@gmail.com (C.S.); nadschneble@freenet.de (N.S.-L.); joerg.mueller@med.uni-jena.de (J.P.M.)
Bauer, Reinhard

(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.

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