Abstract
Under inflammatory conditions, neutrophil apoptosis is delayed due to survival-factor exposure, a mechanism that prevents the resolution of inflammation. One important proinflammatory cytokine involved in the regulation of neutrophil survival/activation is granulocyte–macrophage colony-stimulating factor (GM-CSF). Although GM-CSF mediates antiapoptotic effects in neutrophils, it does not prevent apoptosis, and the survival effect is both time dependent and limited. Here, we identified the proapoptotic Bcl-2 family member Bim as an important lifespan limiting molecule in neutrophils, particularly under conditions of survival factor exposure. Strikingly, GM-CSF induced Bim expression in both human and mouse neutrophils that was blocked by pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). Increased Bim expression was also seen in human immature bone marrow neutrophils as well as in blood neutrophils from septic shock patients; both cell populations are known to be exposed to GM-CSF under in vivo conditions. The functional role of Bim was investigated using Bim-deficient mouse neutrophils in the presence and absence of the survival cytokines interleukin (IL)-3 and GM-CSF. Lack of Bim expression resulted in a much higher efficacy of the survival cytokines to block neutrophil apoptosis. Taken together, these data demonstrate a functional role for Bim in the regulation of neutrophil apoptosis and suggest that GM-CSF and other neutrophil hematopoietins initiate a proapoptotic counterregulation that involves upregulation of Bim.
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Abbreviations
- IL:
-
interleukin
- BimEL:
-
Bim extra long
- BimL:
-
Bim long
- BimS:
-
Bim short
- DLC:
-
dynein light chain
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- Mcl-1:
-
myeloid-cell leukemia sequence 1
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Acknowledgements
We appreciate the help of Dr. C Müller and Dr. E Binda regarding maintaining and genotyping of the mouse strains. We also thank Dr. D Simon (Department of Dermatology, Inselspital, University of Bern), who collected blood samples from control individuals. This work was supported by the Swiss National Science Foundation (Grant no. 310000-107526) and the OPO Foundation, Zurich, Switzerland.
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Andina, N., Conus, S., Schneider, E. et al. Induction of Bim limits cytokine-mediated prolonged survival of neutrophils. Cell Death Differ 16, 1248–1255 (2009). https://doi.org/10.1038/cdd.2009.50
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DOI: https://doi.org/10.1038/cdd.2009.50
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