Early events in spontaneous neutrophil apoptosis

2004 ◽  
Vol 32 (3) ◽  
pp. 461-464 ◽  
Author(s):  
D. Scheel-Toellner ◽  
K.-Q. Wang ◽  
P.R. Webb ◽  
S.H. Wong ◽  
R. Craddock ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Death Receptor ◽  
Current Evidence ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Spontaneous Apoptosis ◽  
Resolution Of Inflammation ◽  
Receptor Signalling ◽  
Apoptotic Protein

Neutrophils are very abundant, short-lived leucocytes and their death by apoptosis is central to homoeostasis and the resolution of inflammation, yet the trigger for apoptosis is still a topic of debate. Depolarization of the mitochondrial membrane has been supposed to initiate neutrophil spontaneous apoptosis, as neutrophils gradually lose the anti-apoptotic protein Mcl-1 and Bax translocates and inserts into the mitochondrial membrane. However, other reports show that caspase 8 is required for neutrophil apoptosis, suggesting the involvement of DR (death receptor) signalling. As DR ligation is not required for neutrophil apoptosis, this raises the intriguing possibility that activation of caspase 8 during neutrophil apoptosis occurs via a novel mechanism. In the present paper, we discuss the current evidence for mechanisms occurring in neutrophil apoptosis, which could trigger DR signalling in the absence of DR ligation.

Clustering of death receptors in lipid rafts initiates neutrophil spontaneous apoptosis

2004 ◽  
Vol 32 (5) ◽  
pp. 679-681 ◽  
Author(s):  
D. Scheel-Toellner ◽  
K. Wang ◽  
L.K. Assi ◽  
P.R. Webb ◽  
R.M. Craddock ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Death Receptor ◽  
Death Receptors ◽  
Acid Sphingomyelinase ◽  
Early Event ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Receptor Signalling ◽  
Blocking Antibodies

Neutrophils die by apoptosis spontaneously within 12–24 h of their release from the bone marrow. The mechanism regulating entry of neutrophils into apoptosis at the end of their life-span is currently under debate. Our data suggest that neutrophil apoptosis involves a novel mechanism of caspase 8 activation that is indirectly regulated by accumulation of reactive oxygen species. We detected early activation of caspase 8 upstream of caspase 3 activation, suggesting death receptor signalling. The CD95 DISC (death-inducing signalling complex) was detected in neutrophils, but blocking antibodies to death receptors did not inhibit apoptosis, suggesting a novel mechanism for caspase 8 activation. Death receptor clustering in ceramide-rich lipid rafts is thought to be an early event in their signalling, so we investigated the role of ceramide generated by ASM (acid sphingomyelinase) in neutrophil apoptosis. Ceramide was generated early in neutrophil apoptosis, and ASM activity was required for neutrophil apoptosis. Moreover, neutrophil apoptosis was significantly delayed in ASM−/− mice compared with their wild-type littermates. CD95 DISC components were present in lipid rafts in neutrophils, and were progressively clustered in cultured neutrophils. Generation of ceramide was blocked by desferrioxamine, suggesting that hydroxyl radicals are important for the activation of ASM. This observation was in line with our earlier observation of a precipitous drop in reduced glutathione in the aging neutrophil.

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

Regulation of neutrophil apoptosis by Mcl-1

2004 ◽  
Vol 32 (3) ◽  
pp. 489-492 ◽  
Author(s):  
S.W. Edwards ◽  
M. Derouet ◽  
M. Howse ◽  
R.J. Moots
Keyword(s):  
Inflammatory Response ◽  
Survival Time ◽  
Inflammatory Cytokines ◽  
Turnover Rate ◽  
Neutrophil Apoptosis ◽  
Spontaneous Apoptosis ◽  
High Turnover ◽  
Apoptotic Protein ◽  
Local Oxygen ◽  
Pro Inflammatory Cytokines

Neutrophils rapidly undergo spontaneous apoptosis, but this process can be considerably delayed by exposure to a variety of agents such as pro-inflammatory cytokines. The anti-apoptotic protein of the Bcl-2 family, Mcl-1, plays a key role in the regulation of neutrophil apoptosis. The protein has some unusual properties compared with other family members, including an extremely high turnover rate. Many factors, such as cytokines and local oxygen concentrations, can regulate cellular levels of Mcl-1 via transcription and post-transcriptional modification, control the survival time of neutrophils within tissues and thereby influence the inflammatory response.

scholarly journals Caspase-8 is activated by cathepsin D-initiating neutrophil apoptosis during the resolution of inflammation

2008 ◽  
Vol 180 (5) ◽  
pp. i14-i14 ◽  
Author(s):  
Sébastien Conus ◽  
Remo Perozzo ◽  
Thomas Reinheckel ◽  
Christoph Peters ◽  
Leonardo Scapozza ◽  
...  
Keyword(s):  
Cathepsin D ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Resolution Of Inflammation

Reactive oxygen species limit neutrophil life span by activating death receptor signaling

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2557-2564 ◽  
Author(s):  
Dagmar Scheel-Toellner ◽  
Keqing Wang ◽  
Rachel Craddock ◽  
Paul R. Webb ◽  
Helen M. McGettrick ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Life Span ◽  
Lipid Rafts ◽  
Death Receptor ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Oxygen Species ◽  
Receptor Signaling ◽  
Death Receptor Signaling ◽  
Ceramide Generation

Abstract Neutrophils are abundant, short-lived leukocytes, and their death by apoptosis is central to hemostasis and the resolution of inflammation, yet the trigger for their entry into apoptosis is unknown. We show here that death receptor signaling, including CD95 death-inducing signaling complex (DISC) formation and caspase 8 activation, occurred early in neutrophil apoptosis. However, death receptor ligation was not required for apoptosis, suggesting a novel mechanism for caspase 8 activation. We detected ceramide generation and clustering of CD95 in lipid rafts early in neutrophil apoptosis, and neutrophil apoptosis and ceramide generation were both significantly inhibited in acid sphingomyelinase knockout (ASM–/–) mice compared to wild-type littermates. Further studies revealed that ceramide generation, CD95 clustering, and neutrophil apoptosis were dependent on reactive oxygen species (ROSs) and were preceded by a fall in reduced glutathione levels. We propose that accumulation of ROSs, as a consequence of altered redox status, initiates ligand-independent death receptor signaling via activation of ASM and clustering of preformed DISC components in lipid rafts and is therefore a primary factor limiting neutrophil life span.

Thermotolerance induced at a fever temperature of 40 °C protects cells against hyperthermia-induced apoptosis mediated by death receptor signalling

2008 ◽  
Vol 86 (6) ◽  
pp. 521-538 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Diana A. Averill-Bates
Keyword(s):  
Chromatin Condensation ◽  
Death Receptor ◽  
Annexin V ◽  
Receptor Activation ◽  
Caspase 8 ◽  
Death Domain ◽  
Adaptive Responses ◽  
Receptor Signalling ◽  
Induced Apoptosis ◽  
Shock Proteins

Mild temperatures such as 40 °C are physiological and occur during fevers. This study determines whether mild thermotolerance induced at 40 °C can protect HeLa cells against activation of the death receptor pathway of apoptosis by lethal hyperthermia (42–45 °C). Protein expression of heat shock proteins (Hsps) 27, 32, 60, 72, 90, and 110 was increased in thermotolerant cells (3 h, 40°C). Lethal hyperthermia (42–43 °C)  caused cell death by apoptosis, but at 45 °C there was a switch to necrosis. Mild thermotolerance protected cells against heat-induced apoptosis (Annexin V labelling). Hyperthermia induced apoptosis through generation of reactive oxygen species (ROS) and death receptor signalling. The antioxidant polyethylene glycol-catalase abrogated increased expression of Fas death ligand and caspase-8 activation in response to lethal hyperthermia (42–43 °C). Mild thermotolerance attenuated the heat induction of ROS and FasL, which were initiating events in death receptor activation and signalling. Mild thermotolerance inhibited early events in hyperthermia-induced death receptor apoptosis such as Fas-associated death domain (FADD) translocation to membranes, caspase-8 activation, and tBid translocation to mitochondria. Downstream events in apoptosis such as caspase-3 activation, cleavage of PARP and ICAD, and chromatin condensation were also diminished in thermotolerant cells. It is important to improve knowledge about adaptive responses induced by exposure to mild stresses, such as fever temperatures, which can protect cells against subsequent exposure to lethal stress.

scholarly journals Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer

Oncogene ◽  
2001 ◽  
Vol 20 (41) ◽  
pp. 5865-5877 ◽  
Author(s):  
Simone Fulda ◽  
Martin U Küfer ◽  
Eric Meyer ◽  
Frans van Valen ◽  
Barbara Dockhorn-Dworniczak ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Death Receptor ◽  
Caspase 8 ◽  
Drug Induced ◽  
Or Gene ◽  
Induced Apoptosis

scholarly journals Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

2014 ◽  
Vol 307 (1) ◽  
pp. L62-L70 ◽  
Author(s):  
Mark T. Kearns ◽  
Lea Barthel ◽  
Joseph M. Bednarek ◽  
Zulma X. Yunt ◽  
Peter M. Henson ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Alveolar Macrophage ◽  
Fas Ligand ◽  
Ex Vivo ◽  
Pulmonary Inflammation ◽  
Death Receptor ◽  
Dependent Manner ◽  
Resolution Of Inflammation ◽  
Macrophage Apoptosis ◽  
Rag 1

Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+T lymphocytes in the resolution of acute pulmonary inflammation.

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