Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa

Susanne Kirschnek (1) , Juliane Vier (1) , Sanjivan Gautam (1) , Tobias Frankenberg (1) , Svetla Rangelova (1) , Pedro Eitz Ferrer (1) , Francesca Grespi (1) , Eleonora Ottina (1) , Andreas Villunger (1) , Hans Haecker (1) , Georg Hacker (1)

1 Institute of Medical Microbiology and Hygiene

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 Bcl-2 family proteins. Spontaneous apoptosis was preceded by down-regulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic BH3-only protein Bim gave some protection but only neutrophils deficient in both BH3-only proteins, Bim and Noxa were strongly protected against apoptosis. The function of Noxa was neutralization of 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 the Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation and is required for the termination of neutrophil function and neutrophil-dependent inflammation.

Mots clés: neutrophil granulocyte; apoptosis; Bcl-2 family; inflammation

Susanne Kirschnek, Juliane Vier, Sanjivan Gautam, Tobias Frankenberg, Svetla Rangelova, et al.. Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.69⟩. ⟨hal-00650358⟩