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

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

Nature communications (2018-03-10)
Lan H Chu, Mohanalaxmi Indramohan, Rojo A Ratsimandresy, Anu Gangopadhyay, Emily P Morris, Denise M Monack, Andrea Dorfleutner, Christian Stehlik
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.

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Anti-GSDMD (126-138) antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution