ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1666184
Phospholipase D1 is a critical mediator of neutrophil extracellular trap formation and venous thrombosis
Provisionally accepted- 1Kyushu Daigaku Seitai Bogyo Igaku Kenkyujo, Fukuoka, Japan
- 2Kyushu Shika Daigaku, Kitakyushu, Japan
- 3Kokuritsu Choju Iryo Kenkyu Center Kenkyujo, Obu, Japan
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Neutrophil extracellular traps (NETs) are a host defense mechanism whereby activated neutrophils release decondensed chromatin and antimicrobial proteins into the extracellular space to trap and kill invading pathogens. While effective in clearing pathogens, NETs also pose pathological risks by exposing self-DNA, histones, granular enzymes, and reactive oxygen species (ROS), contributing to pathologies such as autoimmune diseases, inflammatory disorders, and thrombosis. Here, we identify phospholipase D1 (PLD1), a lipid-signaling enzyme that generates phosphatidic acid (PA), as a critical regulator of ROS generation and NET formation in murine neutrophils. Using both PLD1-deficient neutrophils and a selective inhibitor, we demonstrate that PLD1 is essential for NET release. Notably, exogenous PA alone is sufficient to trigger robust ROS production and NET formation. In vivo, PLD1-deficient mice fail to generate ROS in an acute lung inflammation model and are protected from venous thrombosis. These findings identify PLD1 and PA as key upstream regulators of NET formation and suggest that pharmacological inhibition of PLD1 could provide a potential avenue for early intervention in NET-related diseases such as venous thrombosis.
Keywords: Phospholipase D1, phosphatidic acid, Neutrophil extracellular trap, Reactive Oxygen Species, deep vein thrombosis
Received: 15 Jul 2025; Accepted: 07 Oct 2025.
Copyright: © 2025 Aihara, Takahashi, Morino, Matsuara, Kunimura, Nishikimi, Izumi, Bamba, Fukui and Uruno. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ryosuke Aihara, r21aihara@fa.kyu-dent.ac.jp
Takehito Uruno, uruno@bioreg.kyushu-u.ac.jp
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.