title: Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa.
abstract: 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.
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universität Freiburg, Germany. susanne.kirschnek@uniklinik-freiburg.de
authors.forename: S
authors.initials: S
authors.lastname: Kirschnek
authors.forename: J
authors.initials: J
authors.lastname: Vier
authors.forename: S
authors.initials: S
authors.lastname: Gautam
authors.forename: T
authors.initials: T
authors.lastname: Frankenberg
authors.forename: S
authors.initials: S
authors.lastname: Rangelova
authors.forename: P
authors.initials: P
authors.lastname: Eitz-Ferrer
authors.forename: F
authors.initials: F
authors.lastname: Grespi
authors.forename: E
authors.initials: E
authors.lastname: Ottina
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.forename: H
authors.initials: H
authors.lastname: Häcker
authors.forename: G
authors.initials: G
authors.lastname: Häcker
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009504:Neutrophils / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein