Fibroblast-Derived PLA2G12A Amplifies Mast Cell Activation Through Extracellular Phospholipid Remodeling
6 affiliations
- 1Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (CDBIM), Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- 2Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
- 3Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- 4Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City 230-0045, Kanagawa, Japan
- 5Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512, Japan
- 6Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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.
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BibTeX
@article{taketomi2026fibroblastderived,
title = {{Fibroblast-Derived PLA2G12A Amplifies Mast Cell Activation Through Extracellular Phospholipid Remodeling}},
author = {Yoshitaka Taketomi and Yoshimi Miki and Takayoshi Higashi and Yuki Nagasaki and Kuniyuki Kano and Makoto Arita and Junken Aoki and Makoto Murakami},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201848},
url = {https://www.mdpi.com/2073-4409/15/20/1848},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fibroblast-Derived PLA2G12A Amplifies Mast Cell Activation Through Extracellular Phospholipid Remodeling
AU - Yoshitaka Taketomi
AU - Yoshimi Miki
AU - Takayoshi Higashi
AU - Yuki Nagasaki
AU - Kuniyuki Kano
AU - Makoto Arita
AU - Junken Aoki
AU - Makoto Murakami
PY - 2026
DA - 2026/10/12
JO - Cells
DO - 10.3390/cells15201848
UR - https://www.mdpi.com/2073-4409/15/20/1848
AB - 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.
SN - 2073-4409
ER -