Activation of the NLRP3 inflammasome in microglia
| Autor: | Douglas T. Golenbock, Pilar Martinez-Martinez, Hannah Scheiblich, Michael T. Heneka, Eicke Latz, Anna Schlütter |
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| Přispěvatelé: | RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
PRIMARY NEURONS Inflammasomes metabolism [NLR Family Pyrin Domain-Containing 3 Protein] Interleukin-1beta microglia pharmacology [Ceramides] metabolism [Microglia] drug effects [Microglia] Biochemistry metabolism [Cytoskeletal Proteins] chemistry.chemical_compound Mice INTERLEUKIN-1 RECEPTOR ANTAGONIST IL-1 beta metabolism [Reactive Oxygen Species] Cells Cultured INDUCED APOPTOSIS Microglia Inflammasome Ceramide transport AMYLOID-BETA Cell biology ALZHEIMERS-DISEASE drug effects [Inflammasomes] medicine.anatomical_structure Caspase-1 POTENTIAL ROLE FATTY-ACIDS medicine.drug Ceramide Caspase 1 Nlrp3 protein mouse Biology Ceramides ASC 03 medical and health sciences Cellular and Molecular Neuroscience metabolism [Interleukin-1beta] NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Secretion ddc:610 ceramide Macrophages Serine C-palmitoyltransferase Lipid signaling NLRP3 inflammasome SERINE PALMITOYLTRANSFERASE Cytoskeletal Proteins 030104 developmental biology chemistry CELL-DEATH metabolism [Macrophages] PATTERN-RECOGNITION Carrier Proteins Reactive Oxygen Species metabolism [Inflammasomes] metabolism [Carrier Proteins] |
| Zdroj: | Journal of neurochemistry 143(5), 534-550 (2017). doi:10.1111/jnc.14225 Journal of Neurochemistry, 143(5), 534-550. Wiley |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.14225 |
| Popis: | Inflammation within the CNS is a major component of many neurodegenerative diseases. A characteristic feature is the generation of microglia-derived factors that play an essential role in the immune response. IL-1 beta is a pro-inflammatory cytokine released by activated microglia, able to exacerbate injury at elevated levels. In the presence of caspase-1, pro-IL-1 beta is cleaved to the mature cytokine following NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation. Growing evidence suggests that ceramide plays a critical role in NLRP3 inflammasome assembly, however, the relationship between ceramide and inflammasome activation in microglia remains unknown. Here, we investigated potential mechanistic links between ceramide as a modulator of NLRP3 inflammasome assembly and the resulting secretion of IL-1 beta using small bioactive enzyme stimulators and inhibitors of ceramide signaling in wild-type and apoptosis-associated speck-like protein containing a CARD knockout (ASC(-/-)) primary microglia. To induce the expression of inflammasome components, microglia were primed prior to experiments. Treatment with sodium palmitate (PA) induced de novo ceramide synthesis via modulation of its synthesizing protein serine palmitoyl transferase resulting in increased IL-1 beta secretion in microglia. Exposure of microglia to the serine palmitoyl transferase-inhibitor l-cycloserine significantly prevented PA-induced IL-1 beta secretion. Application of the ceramide analogue C2 and the sphingosine-1-phosphate-receptor agonist Fingolimod (FTY720) up-regulated levels of IL-1 beta and cleaved caspase-1 in wild-type microglia, whereas ASC(-/-) microglia were unaffected. HPA-12 inhibition of ceramide transport did not affect inflammasome activation. Taken together, our findings reveal a critical role for ceramide as a positive modulator of NLRP3 inflammasome assembly and the resulting release of IL-1 beta. |
| Databáze: | OpenAIRE |
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