Deactivation of phosphatidylinositol 3,4,5-trisphosphate/Akt signaling mediates neutrophil spontaneous death.
Neutrophil spontaneous death plays essential roles in neutrophil homeostasis and resolution of inflammation, whereas the underlying molecular mechanisms are still ill-defined. Neutrophils die because of programmed cell death or apoptosis. However, treatment with inhibitor of caspases, which are responsible for the majority of apoptotic cell deaths, does not prevent the spontaneous death of neutrophils. PKB/Akt possesses prosurvival and antiapoptotic activities in a variety of cells. In this study, we show that Akt activity decreases dramatically during the course of neutrophil death. Both phosphatidylinositol 3-kinase and Akt inhibitors enhance neutrophil death. Conditions delaying neutrophil death, such as treatment with granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or IFN-gamma, restore Akt activity. Finally, we demonstrate that neutrophils depleted of PTEN, a phosphatidylinositol 3'-phosphatase that negatively regulates Akt activity, live much longer than WT neutrophils. Thus, we establish Akt deactivation as a causal mediator of neutrophil spontaneous death.
Zhu
Daocheng
D
Department of Pathology, Joint Program in Transfusion Medicine, Harvard Medical School, Boston, MA 02115, USA.
Hattori
Hidenori
H
Jo
Hakryul
H
Jia
Yonghui
Y
Subramanian
Kulandayan K
KK
Loison
Fabien
F
You
Jian
J
Le
Yi
Y
Honczarenko
Marek
M
Silberstein
Leslie
L
Luo
Hongbo R
HR
D000818:Animals; D061945:Caspase Inhibitors; D016923:Cell Death; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000166:cytology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D061945:Caspase Inhibitors; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase