1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine and Peritonitis

The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex consisting of a receptor, an adaptor protein, and procaspase-1 that induces the secretion of the mature form of IL-1β in response to microbial infection and danger signals. Activation of the NLRP3 inflammasome induced by endogenous danger signal molecules is closely linked to the development and progress of chronic inflammatory diseases. The oxidation of phospholipids occurs upon cellular stress and damage, resulting in the accumulation of oxidized phosphatidylcholines (oxPAPC) such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphocholine (POVPC) at inflammatory sites. In this study, we investigated whether oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages, leading to the secretion of IL-1β. POVPC induced the degradation of procaspase-1 to caspase-1(p10), the cleavage of pro-IL-1β to IL-1β, and oligomerization of ASC in primary mouse bone marrow-derived macrophages. POVPC-induced production of caspase-1, and IL-1β was abolished in macrophages derived from NLRP3- or caspase-1-deficient mice. In an air pouch model and a peritonitis model in mice, POVPC injection resulted in the production of caspase-1(p10), IL-1β, and IL-18 in wild-type, but not in NLRP3-deficient, mice. POVPC-induced inflammasome activation was mediated by mitochondrial reactive oxygen species resulting from intracellular Ca

Topics: Animals; Apoptosis Regulatory Proteins; Calcium; CARD Signaling Adaptor Proteins; Caspase 1; Cells, Cultured; Cyclosporine; Disease Models, Animal; Inflammasomes; Interleukin-1beta; Intracellular Space; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Peritonitis; Phagocytosis; Phospholipid Ethers; Potassium; Protein Multimerization; Proteolysis; Reactive Oxygen Species