Work

Calcium-independent phospholipase A2 is a novel regulator of NLRP3 inflammasome activation and pro-inflammatory cytokine release 3889

Year: 2025

Type: article

Abstract: Description Cell membranes are essential for life, establishing barriers between the intracellular and extracellular environment and organizing intracellular organelles. Physical membrane properties, such as fluidity, curvature, and lipid raft formation - key for receptor signaling - are determined by the composition of membrane phospholipids and regulated by enzymes like calcium-independent phospholipase A2 (iPLA2). iPLA2 hydrolyzes phospholipids into lysophospholipids and free fatty acids and is well-known for its role in neurons, where its dysregulation is linked to neurodegenerative diseases like PLA2G6-associated neurodegeneration (PLAN) and Parkinson’s disease. However, its function in immune cells remains poorly understood. Here we show that iPLA2 regulates NLRP3 inflammasome activation and pro-inflammatory cytokine release. siRNA-mediated iPLA2 knockdown in primary human macrophages significantly reduced IL-1β release in response to different NLRP3 activators. This knockdown also decreased NLRP3 and pro-IL-1β expression, inhibited ASC speck formation, and reduced Caspase-1 activation. CRISPR-Cas9-mediated KO of iPLA2 in THP-1 and mouse BMDMs further confirmed a marked reduction in IL-1β release, offering a robust tool for mechanistic studies. Our findings reveal a novel role for iPLA2 in regulating pro-inflammatory immune responses. This highlights its potential involvement in the pathogenesis of neuroinflammatory diseases, expanding its significance beyond the neuronal context. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1636