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

Lan H. Chu, Mohanalaxmi Indramohan, Rojo A. Ratsimandresy, Anu Gangopadhyay, Emily P. Morris, Denise M. Monack, Andrea Dorfleutner () and Christian Stehlik ()
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Lan H. Chu: Northwestern University
Mohanalaxmi Indramohan: Northwestern University
Rojo A. Ratsimandresy: Northwestern University
Anu Gangopadhyay: Northwestern University
Emily P. Morris: Northwestern University
Denise M. Monack: Stanford University, Stanford
Andrea Dorfleutner: Northwestern University
Christian Stehlik: Northwestern University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03409-3

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