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.
Highlights
Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response
Extracellular LPS is chaperoned by CD14 from the LPS-binding protein to the TLR4/ MD-2 transmembrane LPS receptor complex at the cell surface and induces transcription of proinflammatory genes[2,3], intracellular LPS delivered by Gram-negative bacteria escaping the phagosome[4,5,6] or by extracellular bacterial outer membrane vesicles (OMVs)[7] activates the non-canonical inflammasome caspases[8,9]
As the role of oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) in the LPS response is controversial, we first tested the effect on LPS-induced IL-6 production, which is dependent on TLR4
Summary
Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Whereas caspase-1 is activated by the highly regulated canonical inflammasome complex[10,11,12], caspase-11 and the human orthologs caspase-4 and caspase-5 lack an upstream sensory complex, and are activated by directly binding to LPS through the N-terminal caspase recruitment domain (CARD)[13] This activation results in pyroptotic cell death, cytokine release by the canonical inflammasome, and reduced survival in response to LPS-induced shock in a TLR4-independent manner[8,9,14]. Even higher concentrations of the individual oxPAPC components 1-palmitoyl-2-(5’-oxo-valeroyl)sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2- glutaryl-sn-glycero-3-phosphocholine (PGPC) have been suggested to activate caspase-11 and the canonical NLRP3 inflammasome in macrophages[27,28] This finding is in contrast to earlier reports, demonstrating that oxPAPC prevents DC activation, maturation, and cytokine release, and prevents sepsis[25,29]. We report an anti-inflammatory function of oxPAPC in macrophages, which directly binds to caspase-4 and caspase-11, prevents caspase interaction with LPS and thereby inhibits LPSmediated pyroptosis, cytokine release, and septic shock
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