title: Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages.
abstract: Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1β secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1β from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1β release. IL-1β release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation.
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Nadia M
authors: NM
authors: Luheshi
authors: James A
authors: JA
authors: Giles
authors: Gloria
authors: G
authors: Lopez-Castejon
authors: David
authors: D
authors: Brough
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010538:Peritonitis / Q000201:enzymology / Q000276:immunology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000276:immunology; D011897:Random Allocation; D013110:Sphingosine / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D008387:Marine Toxins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010080:Oxazoles; D019319:Okadaic Acid; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D013110:Sphingosine