Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia.
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.
Li
Yitang
Y
Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Children's Hospital Boston, MA, USA.
Jia
Yonghui
Y
Pichavant
Muriel
M
Loison
Fabien
F
Sarraj
Bara
B
Kasorn
Anongnard
A
You
Jian
J
Robson
Bryanne E
BE
Umetsu
Dale T
DT
Mizgerd
Joseph P
JP
Ye
Keqiang
K
Luo
Hongbo R
HR
D000818:Animals; D004927:Escherichia coli Infections / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000401:mortality; D017353:Gene Deletion; D018390:Gene Targeting; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009503:Neutropenia / Q000150:complications / Q000235:genetics* / Q000276:immunology; D018375:Neutrophil Activation / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse