Targeted Deletion of Tumor Suppressor PTEN Augments Neutrophil Function and Enhances Host Defense in Neutropenia-Associated Pneumonia
View/ Open
27-Yitang-blood.pdf (4.208Mb)
Access Status
Full text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.Author
Li, Yitang
Jia, Yonghui
Pichavant, Muriel
Sarraj, Bara
Kasorn, Anongnard
You, Jian
Robson, Bryanne E.
Ye, Keqiang
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1182/blood-2008-06-161414Metadata
Show full item recordCitation
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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pubmed/19286998Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13348326
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)