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Blood, 14 May 2009, Vol. 113, No. 20, pp. 4930-4941. Prepublished online as a Blood First Edition Paper on March 13, 2009; DOI 10.1182/blood-2008-06-161414. This Article Full Text Full Text (PDF) Supplemental Methods and Figures Additional Supplemental Figures All Versions of this Article: blood-2008-06-161414v1 113/20/4930    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Li, Y. Articles by Luo, H. R. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by Luo, H. R. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia Yitang Li1, Yonghui Jia1, Muriel Pichavant2, Fabien Loison1, Bara Sarraj1, Anongnard Kasorn1, Jian You1, Bryanne E. Robson3, Dale T. Umetsu2, Joseph P. Mizgerd3, Keqiang Ye4, and Hongbo R. Luo1 1 Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, and Department of Laboratory Medicine, Children's Hospital Boston, MA; 2 Department of Immunology, Children's Hospital Boston, and Harvard Medical School, MA; 3 Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA; and 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 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)P3) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3'-phosphatase that hydrolyzes PtdIns(3,4,5)P3. 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)P3 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)P3 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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