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

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.

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…21,22 Similar to LPS, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC), an oxidized phospholipid, and lipophosphoglycan produced by Leishmania species have been suggested to activate caspase-11; however, conflicting findings have been reported. [23][24][25][26] The fungal pathogens Aspergillus fumigatus and Paracoccidioides brasiliensis have also been demonstrated to activate the noncanonical inflammasome. 27,28 Accordingly, host and microbial pathogens other than Gram-negative bacteria may also produce ligands for caspase-4, -5, and -11.…”

Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D

“…These results in their ensemble raise the possibility that inflammation pathways are regulated by the oxidative state of a cell, namely by the generation of reactive oxygen species, and by cellular levels of antioxidants like glutathione and thioredoxin. In fact, oxidized endogenous lipids are known to regulate the non-canonical inflammasome [19][20][21] . A number of papers have implicated oxidation in the most studied inflammatory pathway, mediated by the NLRP3 inflammasome [16][17][18]22 .…”

Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections

“…Furthermore, oxPAPC appeared as a caspase‐11 regulator in Mϕ s, but not in DCs. Caspase‐11 binds to oxPAPC competing with cytoplasmic LPS, thus abrogating LPS‐induced pyroptosis and IL‐1β release . Hence, oxPAPC may modulate the noncanonical inflammasome offering a novel therapeutic approach against Gram‐negative bacteria‐induced septic shock.…”