Clustering of death receptors in lipid rafts initiates neutrophil spontaneous apoptosis
| Autor: | Paul Webb, Lakhvir K Assi, Keqing Wang, Janet M. Lord, Mike Salmon, Dagmar Scheel-Toellner, Rachel Craddock |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Ceramide
Time Factors Neutrophils Apoptosis Mice Transgenic Caspase 3 Deferoxamine Biology Ceramides Caspase 8 Models Biological Biochemistry Receptors Tumor Necrosis Factor Mice chemistry.chemical_compound Membrane Microdomains medicine Animals fas Receptor Lipid raft Hydroxyl Radical Fas receptor Glutathione Cell biology Enzyme Activation Sphingomyelin Phosphodiesterase chemistry Caspases Receptor clustering Acid sphingomyelinase Reactive Oxygen Species medicine.drug |
| Zdroj: | Biochemical Society Transactions. 32:679-681 |
| ISSN: | 1470-8752 0300-5127 |
| DOI: | 10.1042/bst0320679 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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