@article{10.1182/blood-2010-08-302059,
    author = {Jun, Hyun Sik and Lee, Young Mok and Song, Ki Duk and Mansfield, Brian C. and Chou, Janice Y.},
    title = {G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis},
    journal = {Blood},
    volume = {117},
    number = {14},
    pages = {3881-3892},
    year = {2011},
    month = {04},
    abstract = {G6PC3 (or glucose-6-phosphatase-β) deficiency underlies a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. Here we show that murine G6pc3−/− neutrophils undergoing ER stress activate protein kinase-like ER kinase and phosphatidylinositol 3,4,5-trisphosphate/Akt signaling pathways, and that neutrophil apoptosis is mediated in part by the intrinsic mitochondrial pathway. In G6PC3-deficient patients, granulocyte colony-stimulating factor (G-CSF) improves neutropenia, but its impact on neutrophil apoptosis and dysfunction is unknown. We now show that G-CSF delays neutrophil apoptosis in vitro by modulating apoptotic mediators. However, G6pc3−/− neutrophils in culture exhibit accelerated apoptosis compared with wild-type neutrophils both in the presence or absence of G-CSF. Limiting glucose (0.6mM) accelerates apoptosis but is more pronounced for wild-type neutrophils, leading to similar survival profiles for both neutrophil populations. In vivo G-CSF therapy completely corrects neutropenia and normalizes levels of p-Akt, phosphatidylinositol 3,4,5-trisphosphate, and active caspase-3. Neutrophils from in vivo G-CSF–treated G6pc3−/− mice exhibit increased glucose uptake and elevated intracellular levels of G6P, lactate, and adenosine-5′-triphosphate, leading to improved functionality. Together, the results strongly suggest that G-CSF improves G6pc3−/− neutrophil survival by modulating apoptotic mediators and rectifies function by enhancing energy homeostasis.},
    issn = {0006-4971},
    doi = {10.1182/blood-2010-08-302059},
    url = {https://doi.org/10.1182/blood-2010-08-302059},
    eprint = {https://ashpublications.org/blood/article-pdf/117/14/3881/1337425/zh801411003881.pdf},
}