Activation of the NLRP3 inflammasome in microglia: the role of ceramide

Hannah Scheiblich, Anna Schlütter, Douglas T. Golenbock, Eicke Latz, Pilar Martinez-Martinez, Michael T. Heneka*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

71 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)534-550
Number of pages17
JournalJournal of Neurochemistry
Volume143
Issue number5
DOIs
Publication statusPublished - Dec 2017

Keywords

  • ASC
  • Caspase-1
  • ceramide
  • IL-1 beta
  • microglia
  • NLRP3 inflammasome
  • INTERLEUKIN-1 RECEPTOR ANTAGONIST
  • ALZHEIMERS-DISEASE
  • SERINE PALMITOYLTRANSFERASE
  • AMYLOID-BETA
  • PATTERN-RECOGNITION
  • INDUCED APOPTOSIS
  • PRIMARY NEURONS
  • POTENTIAL ROLE
  • FATTY-ACIDS
  • CELL-DEATH

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