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

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

Author information

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. a-dorfleutner@northwestern.edu.
5
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA. c-stehlik@northwestern.edu.
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. c-stehlik@northwestern.edu.

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.

PMID:
29520027
PMCID:
PMC5843631
DOI:
10.1038/s41467-018-03409-3
[Indexed for MEDLINE]
Free PMC Article

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