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oaioai:dash.harvard.edu:1/13320258

Neutrophil Spontaneous Death Is Mediated by Down-Regulation of Autocrine Signaling through GPCR, PI3Kγ\gamma, ROS, and actin

Abstract

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 PI3KγPI3K\gamma, 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 PI3KγPI3K\gamma activation via G protein–coupled receptors. Unlike in other cell types, serum-derived growth factors did not provide any survival advantage in neutrophils. PI3KγPI3K\gamma, but not class IA PI3Ks, was negatively regulated by gradually accumulated ROS in apoptotic neutrophils, which suppressed PI3KγPI3K\gamma 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

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Harvard University - DASH

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oaioai:dash.harvard.edu:1/13320258Last time updated on 2/6/2015View original full text link

This paper was published in Harvard University - DASH .

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