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

Abstract

Abstract Inflammasomes are signaling complexes that link the recognition of pathogen and danger associated molecular patterns (PAMPs and DAMPs) by cytosolic pattern-recognition receptors (PPRs) to the activation of Caspase-1, leading to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and the induction of pyroptosis. In addition to the canonical inflammasome activation by Caspase-1, other inflammatory caspases including murine Caspase-11 and its human orthologs Caspase-4 and Caspase-5 participate in the non-canonical pathway in response to intracellular LPS and Gram negative bacteria escaping the phagosomes, resulting in pyroptotic cell death as well as NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for Caspase-1 activation in the canonical inflammasomes, non-canonical inflammatory caspases are directly activated by binding to LPS thus simultaneously act as innate sensors and effectors. It is still largely unknown how the activity of these caspases is regulated. Here we identified the oxidized phospholipid 1-Palmitoyl-2-arachidonoyl-sn- glycero-3-phosphorylcholine (oxPAPC) as a negative regulator of the non-canonical inflammasome in macrophages. In addition to its previously reported TLR4 antagonistic role, oxPAPC directly binds to Caspase-4 and Caspase-11, competes with LPS binding and consequently, inhibits LPS-induced pyroptosis, IL-1β release and septic shock in vivo. Therefore, oxPAPC and its derivatives could provide a basis for novel therapies targeting non-canonical inflammasomes during Gram-negative bacterial sepsis.