Induction of Bim limits cytokine-mediated prolonged survival of neutrophils

Andina, Nicola; Conus, Sébastien; Schneider, E. M.; Fey, Martin F.; Simon, Hans‐Uwe

doi:10.1038/cdd.2009.50

Cited by 47 publications

(51 citation statements)

References 50 publications

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“…The inflammatory milieu is rich in extracellular signals that are known to increase expression of prosurvival Bcl-2 family proteins. Stimulation of neutrophils with Toll-like receptor (TLR) ligands, such as LPS, or inflammatory cytokines, such as G-CSF and GM-CSF, induces Mcl-1 and A1, reduces the expression of proapoptotic proteins such as Bax, and increases Bim expression (16,18,34). Increased levels of G-CSF and GM-CSF have been found in broncho-alveolar lavage cell supernatants from patients with neutrophilic lung inflammation, such as cystic fibrosis, idiopathic fibrosis, pneumonia, and acute allergic alveolitis, but not in individuals without neutrophilic lung inflammation (18).…”

Section: Discussionmentioning

confidence: 99%

Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1

Croker

O’Donnell

Nowell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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During immune responses, neutrophils must integrate survival and death signals from multiple sources to regulate their lifespan. Signals that activate either the Bcl-2- or death receptor-regulated apoptosis pathways can provide powerful stimuli for neutrophils to undergo cell death, but whether they act cooperatively in parallel or directly cross-talk in neutrophils is not known. Previous studies suggested that Bcl-2 family proteins are not required for Fas-induced cell death in neutrophils, but did not examine whether they could modulate its rapid onset. By monitoring the rate of change in neutrophil viability associated with activation of the Fas-triggered death receptor pathway using real-time cell imaging, we show that the Bcl-2-related proteins Bid, Bax, and Bak accelerate neutrophil apoptosis but are not essential for cell death. Increased Bcl-2 or Mcl-1 expression prevents efficient induction of apoptosis by Fas stimulation indicating that the Bcl-2-regulated apoptosis pathway can directly interfere with Fas-triggered apoptosis. Fas has been shown to initiate NFκB activation and gene transcription in cell lines, however gene transcription is not altered in Fas-activated Bid −/− neutrophils, indicating that apoptosis occurs independently of gene transcription in neutrophils. The specification of kinetics of neutrophil apoptosis by Bid impacts on the magnitude of neutrophil IL-1β production, implicating a functional role for the Bcl-2-regulated pathway in controlling neutrophil responses to FasL. These data demonstrate that the intrinsic apoptosis pathway directly controls the kinetics of Fas-triggered apoptosis in neutrophils.

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Section: Discussionmentioning

confidence: 99%

Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1

Croker

O’Donnell

Nowell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, Bim induction does not necessarily correlate with its activation, as was previously demonstrated for lipopolysaccharide-or granuloyte-macrophage colony-stimulating factor-induced survival. 29,30 Neutrophils in the Hoxb8 system differentiate from progenitors that morphologically resemble early promyelocytes. In these cells, the effect of the loss of Bim or Noxa alone was marginal but a very strong effect was seen when both were missing.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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International audienceNeutrophils 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

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“…The active process has been considered to be the depletion of antiapoptotic proteins allowing their pro-apoptotic counterparts to become effectors almost by default. Recently, it has been demonstrated that Bim plays an important role in the induction of apoptosis in neutrophils stimulated towards enhanced longevity by cytokines such as GM-CSF and IL-3 [22]. Bim was shown to be actively transcribed in the presence of pro-survival cytokines, a finding that was ascribed to a novel function as a physiological brake on cytokine-mediated enhanced neutrophil longevity.…”

Section: Introductionmentioning

confidence: 99%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly, NF-jB and MAPK pathways and key endogenous survival proteins (typified by Mcl-1) are involved in the regulation of neutrophil apoptosis and, in cancer-cell lines, have been implicated as possible targets of CDK inhibitors. Here, we demonstrate that R-roscovitine over-rides TNF-a and LPS-induced survival (determined by morphological examination and binding of fluorescently labelled annexin-V) of isolated peripheral blood neutrophils. This effect did not appear to be mediated via effects on early markers of neutrophil activation (e.g. surface marker expression, shape change, aggregation and superoxide anion generation), by direct inhibition of NF-jB activation (assessed by cytoplasmic IjBa proteolysis and NF-jB p65 subunit translocation) and ERK activation (determined by specific ERK phosphorylation) but due to down-regulation (at protein and mRNA level) of the survival protein Mcl-1 but not the pro-apoptotic bcl-2 homologue Bim. These findings suggest that key endogenous survival proteins may be the targets of CDK inhibitors and consequently may be of critical importance in the resolution of inflammation.

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Induction of Bim limits cytokine-mediated prolonged survival of neutrophils

Cited by 47 publications

References 50 publications

Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1

Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1

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

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

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