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Fibroblast-Derived PLA2G12A Amplifies Mast Cell Activation Through Extracellular Phospholipid Remodeling

Year: 2026

Type: article

Abstract: Extracellular vesicles (EVs) mediate intercellular communication, yet whether extracellular phospholipid metabolism on EV membranes regulates immune activation remains incompletely understood. Through comparative phenotypic analyses of multiple secreted phospholipase A2 (sPLA2)-deficient mouse strains, we identified PLA2G12A as a stromal regulator of extracellular lipid metabolism that promotes IgE/antigen-dependent mast cell activation. Pla2g12a deficiency attenuated passive cutaneous and systemic anaphylaxis and selectively impaired IgE-dependent, but not IgE-independent, mast cell responses. Single-cell RNA-sequencing of mouse and human skin revealed that PLA2G12A is expressed in broad subsets of stromal fibroblasts, including papillary fibroblasts adjacent to mast cells, implicating a specialized stromal niche in mast cell regulation. Consistently, mast cell-intrinsic PLA2G12A was dispensable, whereas fibroblast-targeted deletion of Pla2g12a phenocopied global Pla2g12a deficiency. Lipidomic analyses during IgE-mediated anaphylaxis revealed a significant reduction in lysophospholipids, accompanied by minimal changes in oxylipins, in Pla2g12a-deficient skin. Mechanistically, fibroblast-derived PLA2G12A hydrolyzed phospholipids in EV-enriched fractions to generate multiple lysophospholipids, and treatment with either the PLA2G12A-treated EV-enriched fraction or exogenous lysophospholipids restored impaired IgE-dependent anaphylactic responses in Pla2g12a-deficient mice. Collectively, these findings establish sPLA2-driven extracellular phospholipid remodeling as a mechanism by which stromal niches regulate allergic inflammation.

Source: Cells

DOI: 10.3390/cells15201848