Journal
CELL DEATH AND DIFFERENTIATION
Volume 18, Issue 11, Pages 1805-1814Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.69
Keywords
neutrophil granulocyte; apoptosis; Bcl-2 family; inflammation
Categories
Funding
- Deutsche Forschungsgesellschaft [SFB 576]
- American Lebanese Syrian Associated Charities (ALSAC)
- Excellence Initiative of the German Federal
- State Governments (Spemann Graduate School) [GSC-4]
- postgraduate program
- Molecular Cell Biology & Oncology (MCBO)
- Austrian Science Fund (FWF)
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Neutrophils enter the peripheral blood from the bone marrow and die after a short time. Molecular analysis of spontaneous neutrophil apoptosis is difficult as these cells die rapidly and cannot be easily manipulated. We use conditional Hoxb8 expression to generate mouse neutrophils and test the regulation of apoptosis by extensive manipulation of B-cell lymphoma protein 2 (Bcl-2)-family proteins. Spontaneous apoptosis was preceded by downregulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic Bcl-2 homology domain (BH3)-only protein Bcl-2-interacting mediator of cell death (Bim) gave some protection, but only neutrophils deficient in both BH3-only proteins, Bim and Noxa, were strongly protected against apoptosis. Function of Noxa was at least in part neutralization of induced myeloid leukemia cell differentiation protein (Mcl-1) in neutrophils and progenitors. Loss of Bim and Noxa preserved neutrophil function in culture, and apoptosis-resistant cells remained in circulation in mice. Apoptosis regulated by Bim- and Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation, required for the termination of neutrophil function and neutrophil-dependent inflammation. Cell Death and Differentiation (2011) 18, 1805-1814; doi: 10.1038/cdd.2011.69; published online 10 June 2011
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