The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)-trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol ( IntroductionSevere infection frequently occurs when the number of neutrophils in the blood is too low (neutropenia). 1,2 The blood of healthy adults contains approximately 1500 to 7000 neutrophils/mm 3 . Neutropenia is defined as an absolute neutrophil count (ANC) of Ͻ 1500/mm 3 for non-African Americans, or Ͻ 1200/mm 3 for African Americans. The risk of infection begins to increase at an ANC Ͻ1000/mm 3 . It is considered as severe neutropenia when the ANC falls below 500/mm 3 . One common cause of severe neutropenia is chemotherapy, which is extensively used to treat various hematologic malignancies and solid tumors. Neutropenia-associated infection is the most important dose-limiting toxicity of this therapeutic treatment, impacting on the quality of life and clinical outcomes, with the potential to cause death. [1][2][3] Neutropenia-related infections have been treated with broadspectrum antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) therapy. However, not all patients respond to antibiotic treatment. G-CSF therapy often does not work before the bone marrow is recovered and is associated with side effects such as bone pain, headache, fatigue, and nausea. [1][2][3][4] Granulocyte transfusion also has been considered a therapeutic modality for lifethreatening bacterial and fungal infections in severe neutropenic patients. [5][6][7][8] The possibility of enhancing host immune defenses by infusion of neutrophil has been explored for Ͼ 70 years. Numerous studies demonstrated that transfusion of granulocyte concentrates obtained without growth factor stimulation or G-CSF-mobilized neutrophils is of benefit f...

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