Targeted Deletion of Tumor Suppressor PTEN Augments Neutrophil Function and Enhances Host Defense in Neutropenia-Associated Pneumonia

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Targeted Deletion of Tumor Suppressor PTEN Augments Neutrophil Function and Enhances Host Defense in Neutropenia-Associated Pneumonia

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Title: Targeted Deletion of Tumor Suppressor PTEN Augments Neutrophil Function and Enhances Host Defense in Neutropenia-Associated Pneumonia
Author: Li, Yitang; Jia, Yonghui; Pichavant, Muriel; Loison, Fabien; Sarraj, Bara; Kasorn, Anongnard; You, Jian; Robson, Bryanne E.; Umetsu, Dale; Mizgerd, Joseph P.; Ye, Keqiang; Luo, Hongbo

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Citation: Li, Yitang, Yonghui Jia, Muriel Pichavant, Fabien Loison, Bara Sarraj, Anongnard Kasorn, Jian You, et al. 2009. “Targeted Deletion of Tumor Suppressor PTEN Augments Neutrophil Function and Enhances Host Defense in Neutropenia-Associated Pneumonia.” Blood 113 (20) (March 13): 4930–4941. doi:10.1182/blood-2008-06-161414. http://dx.doi.org/10.1182/blood-2008-06-161414.
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Abstract: Neutropenia and related infections are the most important dose-limiting toxicities in anticancer chemotherapy and radiotherapy. In this study, we explored a new strategy for augmenting host defense in neutropenia-related pneumonia. Phosphatidylinositol-3,4,5-trisphosphate \((PtdIns(3,4,5)P_3)\) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3'-phosphatase that hydrolyzes \(PtdIns(3,4,5)P_3\). In myeloid-specific PTEN knockout mice, significantly more neutrophils were recruited to the inflamed lungs during neutropenia-associated pneumonia. Using an adoptive transfer technique, we demonstrated that this enhancement could be caused directly by PTEN depletion in neutrophils. In addition, disruption of PTEN increased the recruitment of macrophages and elevated proinflammatory cytokines/chemokine levels in the inflamed lungs, which could also be responsible for the enhanced neutrophil recruitment. Depleting PTEN also significantly delayed apoptosis and enhanced the bacteria-killing capability of the recruited neutrophils. Finally, we provide direct evidence that enhancement of neutrophil function by elevating \(PtdIns(3,4,5)P_3\) signaling can alleviate pneumonia-associated lung damage and decrease pneumonia-elicited mortality. Collectively, these results not only provide insight into the mechanism of action of PTEN and \(PtdIns(3,4,5)P_3\) signaling pathway in modulating neutrophil function during lung infection and inflammation, but they also establish PTEN and related pathways as potential therapeutic targets for treating neutropenia-associated pneumonia.
Published Version: doi:10.1182/blood-2008-06-161414
Other Sources: http://www.ncbi.nlm.nih.gov/pubmed/19286998
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13348326
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