The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages

Nat Commun. 2018 Mar 8;9(1):996. doi: 10.1038/s41467-018-03409-3.

Abstract

Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Caspases / genetics
  • Caspases / immunology
  • Cells, Cultured
  • Female
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Lipopolysaccharides / adverse effects
  • Lipopolysaccharides / immunology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Phosphatidylcholines / administration & dosage*
  • Shock, Septic / genetics
  • Shock, Septic / immunology
  • Shock, Septic / prevention & control*

Substances

  • Anti-Inflammatory Agents
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Phosphatidylcholines
  • oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine
  • Casp4 protein, mouse
  • Caspases