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Targeted deletion of tumor suppressor PTEN enhances neutrophil function and prevents neutropenia‐associated pneumonia
Author(s) -
Li Yitang,
Jia Yonghui,
Pichavant Muriel,
You Jian,
Robson Bryanne,
Umetsu Dale,
Mizgerd Joseph,
Ye Keqiang,
Luo Hongbo
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.495
Subject(s) - pten , neutropenia , pneumonia , immunology , medicine , cancer research , inflammation , signal transduction , biology , pi3k/akt/mtor pathway , chemotherapy , microbiology and biotechnology
Neutropenia and related infections are the most important dose limiting toxicities in anti‐cancer chemo and radiotherapy. In this study, we explored a new strategy for treating/preventing neutropenia‐associated pneumonia. PtdIns(3,4,5)P3 signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3’‐phosphatase that hydrolyzes PtdIns(3,4,5)P3. The recruitment of PTEN null neutrophils to the inflamed lungs was significantly enhanced in neutropenia‐related pneumonic mice. In addition, depleting PTEN significantly delayed neutrophil spontaneous death in the lungs and PTEN null neutrophils also possessed an enhanced bacteria killing capability. Finally, we provided direct evidence that enhancement of neutrophil function by elevating PtdIns(3,4,5)P3‐signaling can alleviate pneumonia‐associated lung damages 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 signal pathway in modulating neutrophil function in lung infection and inflammation, but also establish PTEN and related pathways as novel therapeutic targets for treatment of neutropenia‐associated pneumonia.