Premium
Activation of the NLRP 3 inflammasome in microglia: the role of ceramide
Author(s) -
Scheiblich Hannah,
Schlütter Anna,
Golenbock Douglas T.,
Latz Eicke,
MartinezMartinez Pilar,
Heneka Michael T.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14225
Subject(s) - inflammasome , microglia , caspase 1 , ceramide , microbiology and biotechnology , lipid signaling , pyrin domain , inflammation , chemistry , biology , biochemistry , immunology , apoptosis
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 ‐1β is a pro‐inflammatory cytokine released by activated microglia, able to exacerbate injury at elevated levels. In the presence of caspase‐1, pro‐ IL ‐1β is cleaved to the mature cytokine following NOD‐like receptor pyrin domain containing 3 ( NLRP 3) inflammasome activation. Growing evidence suggests that ceramide plays a critical role in NLRP 3 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 NLRP 3 inflammasome assembly and the resulting secretion of IL ‐1β 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 ‐1β secretion in microglia. Exposure of microglia to the serine palmitoyl transferase‐inhibitor l ‐cycloserine significantly prevented PA ‐induced IL ‐1β secretion. Application of the ceramide analogue C2 and the sphingosine‐1‐phosphate‐receptor agonist Fingolimod ( FTY 720) up‐regulated levels of IL ‐1β 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 NLRP 3 inflammasome assembly and the resulting release of IL ‐1β.