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.
Lan H Chu  1  2 ,  Mohanalaxmi Indramohan  1 ,  Rojo A Ratsimandresy  1 ,  Anu Gangopadhyay  1  2 ,  Emily P Morris  1 ,  Denise M Monack  3 ,  Andrea Dorfleutner  4 ,  Christian Stehlik  5  6
Affiliations
  • 1. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA.
  • 2. Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA.
  • 3. Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, Stanford, California, 94305, USA.
  • 4. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA. [email protected].
  • 5. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA. [email protected].
  • 6. Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA. [email protected].
PMID: 29520027 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.