Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages

Eur J Immunol. 2012 Mar;42(3):716-25. doi: 10.1002/eji.201142079. Epub 2011 Dec 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carrier Proteins / immunology*
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Inflammasomes / immunology*
  • Interleukin-1beta / immunology*
  • Macrophages, Peritoneal / immunology
  • Marine Toxins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Okadaic Acid / pharmacology
  • Oxazoles / pharmacology
  • Peritonitis / enzymology
  • Peritonitis / immunology*
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / immunology
  • Random Allocation
  • Sphingosine / immunology*


  • Carrier Proteins
  • Enzyme Inhibitors
  • Inflammasomes
  • Interleukin-1beta
  • Marine Toxins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Oxazoles
  • Okadaic Acid
  • calyculin A
  • Phosphoprotein Phosphatases
  • Sphingosine