| First Author | Jun HS | Year | 2011 |
| Journal | Blood | Volume | 117 |
| Issue | 14 | Pages | 3881-92 |
| PubMed ID | 21292774 | Mgi Jnum | J:172849 |
| Mgi Id | MGI:5009115 | Doi | 10.1182/blood-2010-08-302059 |
| Citation | Jun HS, et al. (2011) G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis. Blood 117(14):3881-92 |
| abstractText | G6PC3 (or glucose-6-phosphatase-beta) 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. |
