Secreted phospholipase PLA2G12A-driven lysophospholipid signaling via lipolytic modification of extracellular vesicles facilitates pathogenic Th17 differentiation

Mochizuki, C.; Taketomi, Y.; Irie, A.; Kano, K.; Nagasaki, Y.; Miki, Y.; Ono, T.; Nishito, Y.; Nakajima, T.; Tomabechi, Y.; Hanada, K.; Shirouzu, M.; Watanabe, T.; Hata, K.; Izumi, Y.; Bamba, T.; Chun, J.; Kudo, K.; Kotani, A.; Endo, Y.; Aoki, J.; Murakami, M.

doi:10.1101/2024.10.27.620543

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bioRxiv · 10.1101/2024.10.27.620543

Secreted phospholipase PLA2G12A-driven lysophospholipid signaling via lipolytic modification of extracellular vesicles facilitates pathogenic Th17 differentiation

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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 A2 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 ROR{gamma}t activator 1-oleoyl-lysophosphatidylethanolamine. These lysophospholipids are further converted by autotaxin to lysophosphatidic acid (LPA), which assists Th17 differentiation mainly via LPA2 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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Mochizuki, C., Taketomi, Y., Irie, A., Kano, K., Nagasaki, Y., Miki, Y., Ono, T., Nishito, Y., Nakajima, T., Tomabechi, Y., Hanada, K., Shirouzu, M., Watanabe, T., Hata, K., Izumi, Y., Bamba, T., Chun, J., Kudo, K., Kotani, A., Endo, Y., Aoki, J., Murakami, M.. 2024-10-29. Secreted phospholipase PLA2G12A-driven lysophospholipid signaling via lipolytic modification of extracellular vesicles facilitates pathogenic Th17 differentiation. https://doi.org/10.1101/2024.10.27.620543

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