Neutrophil spontaneous death is mediated by down-regulation of autocrine signaling through GPCR, PI3Kgamma, ROS, and actin.
Neutrophil spontaneous apoptosis plays a crucial role in neutrophil homeostasis and the resolution of inflammation. We previously established Akt deactivation as a key mediator of this tightly regulated cellular death program. Nevertheless, the molecular mechanisms governing the diminished Akt activation were not characterized. Here, we report that Akt deactivation during the course of neutrophil spontaneous death was a result of reduced PtdIns(3,4,5)P3 level. The phosphatidylinositol lipid kinase activity of PI3Kgamma, but not class IA PI3Ks, was significantly reduced during neutrophil death. The production of PtdIns(3,4,5)P3 in apoptotic neutrophils was mainly maintained by autocrinely released chemokines that elicited PI3Kgamma activation via G protein-coupled receptors. Unlike in other cell types, serum-derived growth factors did not provide any survival advantage in neutrophils. PI3Kgamma, but not class IA PI3Ks, was negatively regulated by gradually accumulated ROS in apoptotic neutrophils, which suppressed PI3Kgamma activity by inhibiting an actin-mediated positive feedback loop. Taken together, these results provide insight into the mechanism of neutrophil spontaneous death and reveal a cellular pathway that regulates PtdIns(3,4,5)P3/Akt in neutrophils.
Xu
Yuanfu
Y
Institute of Hematology, National Laboratory of Experimental Hematology, Tianjin 30020, China.
Loison
Fabien
F
Luo
Hongbo R
HR
D000199:Actins / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001345:Autoradiography; D015153:Blotting, Western; D058544:Class Ib Phosphatidylinositol 3-Kinase; D015536:Down-Regulation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D000199:Actins; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human