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Peer-reviewedCC BY-NCCell Reports

PLA2G12A-driven extracellular vesicle-lipid signaling amplifies pathogenic T cell responses in inflammatory diseases

  • Chika Mochizuki-Ono1
  • Yoshitaka Taketomi1
  • Atsushi Irie2
  • Kuniyuki Kano3
  • Yuki Nagasaki1
  • Yoshimi Miki1
  • Takashi Ono4
  • Yasumasa Nishito5
  • Takahiro Nakajima6
  • Yuri Tomabechi7
  • Kazuharu Hanada7
  • Mikako Shirouzu7
10 more authors
  • Takashi Watanabe8
  • Kosuke Hata9
  • Yoshihiro Izumi9
  • Takeshi Bamba9
  • Jerold J. M. Chun10
  • Kai Kudo11
  • Ai Kotani12
  • Yusuke Endo6
  • Junken Aoki3
  • Makoto Murakami13
13 affiliations
  1. 1Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
  2. 2Calpain Project, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
  3. 3Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8654, Japan
  4. 4Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
  5. 5Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
  6. 6Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan
  7. 7Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
  8. 8RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan
  9. 9Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
  10. 10Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
  11. 11Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
  12. 12Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan; Department of Regulation of Infectious Cancers, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
  13. 13Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 260-8670, Japan. Electronic address: [email protected]
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Abstract

Lipogenesis-driven metabolic flux is crucial for differentiation of pathogenic Th17 cells. Although our previous CRISPR-based screening identified PLA2G12A as a key player in this process, it has remained obscure how this secreted phospholipase A 2 isoform controls Th17 differentiation. Here we show that global, T cell-specific, or fibroblast-specific deletion of PLA2G12A prevents Th17 differentiation and associated diseases including psoriasis and arthritis. PLA2G12A acts on Th17-derived extracellular vesicles (EVs) to produce lysophospholipids including the RORγt activator 1-oleoyl-lysophosphatidylethanolamine. These lysophospholipids are further converted by autotaxin to lysophosphatidic acid (LPA), which assists Th17 differentiation mainly via LPA 2 receptor. Moreover, PLA2G12A promotes the secretion and uptake of EVs by Th17 cells and alters their cargo contents. Defective Th17 differentiation by PLA2G12A deficiency is rescued by supplementation with PLA2G12A-modified EVs. Importantly, a PLA2G12A-blocking antibody prevents Th17 differentiation and ameliorates psoriasis and arthritis models. Thus, targeting the PLA2G12A-EV-lysophospholipid axis may be useful for treatment of Th17-related diseases.

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Cite

BibTeXRIS
BibTeX
@article{mochizukiono2026pla2g12adriven,
  title = {{PLA2G12A-driven extracellular vesicle-lipid signaling amplifies pathogenic T cell responses in inflammatory diseases}},
  author = {Chika Mochizuki-Ono and Yoshitaka Taketomi and Atsushi Irie and Kuniyuki Kano and Yuki Nagasaki and Yoshimi Miki and Takashi Ono and Yasumasa Nishito and Takahiro Nakajima and Yuri Tomabechi and Kazuharu Hanada and Mikako Shirouzu and Takashi Watanabe and Kosuke Hata and Yoshihiro Izumi and Takeshi Bamba and Jerold J. M. Chun and Kai Kudo and Ai Kotani and Yusuke Endo and Junken Aoki and Makoto Murakami},
  journal = {Cell Reports},
  year = {2026},
  month = jun,
  doi = {10.1016/j.celrep.2026.117391},
  url = {https://doi.org/10.1016/j.celrep.2026.117391},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - PLA2G12A-driven extracellular vesicle-lipid signaling amplifies pathogenic T cell responses in inflammatory diseases
AU  - Chika Mochizuki-Ono
AU  - Yoshitaka Taketomi
AU  - Atsushi Irie
AU  - Kuniyuki Kano
AU  - Yuki Nagasaki
AU  - Yoshimi Miki
AU  - Takashi Ono
AU  - Yasumasa Nishito
AU  - Takahiro Nakajima
AU  - Yuri Tomabechi
AU  - Kazuharu Hanada
AU  - Mikako Shirouzu
AU  - Takashi Watanabe
AU  - Kosuke Hata
AU  - Yoshihiro Izumi
AU  - Takeshi Bamba
AU  - Jerold J. M. Chun
AU  - Kai Kudo
AU  - Ai Kotani
AU  - Yusuke Endo
AU  - Junken Aoki
AU  - Makoto Murakami
PY  - 2026
DA  - 2026/06/01
JO  - Cell Reports
DO  - 10.1016/j.celrep.2026.117391
UR  - https://doi.org/10.1016/j.celrep.2026.117391
AB  - Lipogenesis-driven metabolic flux is crucial for differentiation of pathogenic Th17 cells. Although our previous CRISPR-based screening identified PLA2G12A as a key player in this process, it has remained obscure how this secreted phospholipase A 2 isoform controls Th17 differentiation. Here we show that global, T cell-specific, or fibroblast-specific deletion of PLA2G12A prevents Th17 differentiation and associated diseases including psoriasis and arthritis. PLA2G12A acts on Th17-derived extracellular vesicles (EVs) to produce lysophospholipids including the RORγt activator 1-oleoyl-lysophosphatidylethanolamine. These lysophospholipids are further converted by autotaxin to lysophosphatidic acid (LPA), which assists Th17 differentiation mainly via LPA 2 receptor. Moreover, PLA2G12A promotes the secretion and uptake of EVs by Th17 cells and alters their cargo contents. Defective Th17 differentiation by PLA2G12A deficiency is rescued by supplementation with PLA2G12A-modified EVs. Importantly, a PLA2G12A-blocking antibody prevents Th17 differentiation and ameliorates psoriasis and arthritis models. Thus, targeting the PLA2G12A-EV-lysophospholipid axis may be useful for treatment of Th17-related diseases.
SN  - 2211-1247
SN  - 2639-1856
ER  -