Oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages

Abstract

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 signaling and mitochondrial destabilization. Our results demonstrate that endogenously produced oxidized phosphatidylcholines such as POVPC induce the activation of NLRP3 inflammasome, leading to the production of IL-1β in macrophages. The results provide an insight to understand how the oxidized lipids endogenously produced upon cellular stress and tissue damage contribute to the inflammatory reaction at pathologic sites.

Leishmania donovani inhibits inflammasome‐dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2

“…Release of the biologically active IL-1b requires the expression and activation of inflammasome complex, among which the most well-documented one is NLRP3. Activation of the NLRP3 inflammasome complex appears to be dependent on types of cells involved and is effected by a diverse range of stimuli, including microbe-derived products (54), environmental factors (55), and endogenous molecules (56). Reports have indicated that the NLRP3 inflammasome confers protection against L. amazonensis infection in resistant C57BL/6 mice (57), whereas L. major and L. mexicana could significantly inhibit NLRP3 inflammasome function and IL-1b production (58).…”

Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout

“…Confocal microscopy analysis was performed as previously described29. Briefly, BMDMs were plated on coverslips and incubated with an anti-ASC antibody, then incubated with an anti-rabbit IgG-FITC antibody.…”

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

“…PAMPs derive from bacteria, fungi, or other non-human organisms and can become prevalent in metabolic system and fatty liver disease as a result of perturbations of the microbiome. Blocking Cyp D and mPT-mediated cellular damage can suppress oxidized phosphatidylcholine (DAMP)-mediated and LPS (PAMP)-mediated inflammasome activity in macrophages [183][184][185].…”