Analysis of molecular mechanisms of lipid peroxidation-dependent NET formation

• Project/Area Number: 19K08894
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Yotsumoto Satoshi 東京薬科大学, 生命科学部, 助教 (30318191)
• Co-Investigator(Kenkyū-buntansha): どど 孝介 国立研究開発法人理化学研究所, 開拓研究本部, 専任研究員 (20415243)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 好中球 / 好中球細胞外トラップ / 脂質酸化 / 酸化リン脂質 / ミエロペルオキシダーゼ / 好中球エラスターゼ / チロシンキナーゼ

Outline of Research at the Start

好中球におけるリン脂質酸化制御に関わる分子を同定することができれば、これまで明らかにされていなかった好中球細胞外トラップ（NET)が関与する疾患の発症機序の解明に大きな前進をもたらすと考えられる。さらに、 本研究を発端として、酸化リン脂質の作用を標的としたNET形成阻害剤を開発することができれば、現行の薬物治療とは異なる新たな治療戦略につながる可能性がある。

Outline of Final Research Achievements

Neutrophil extracellular traps (NETs) are released from neutrophils undergoing NETosis, a neutrophil-specific cell death mode. It is well known that production of reactive oxygen species (ROS) triggers NETosis and NET formation. However, details of intracellular signaling downstream of ROS production during NETosis and NET formation remains uncertain. Here, we demonstrated that the peroxidation of phospholipids (PLs) plays a critical role in NETosis and NET formation. PL peroxidation is mediated by the enzymatic activity of myeloperoxidase (MPO). On the other hand, neutrophil elastase (NE), which was previously reported to be released from granules to cytosol by MPO during NET formation, is not required for either the peroxidation of PLs or the execution of NETosis, but contributes to chromatin decondensation and nuclear swelling. These findings indicate the dual roles of MPO in NETosis and NET formation, and provide new insight into the molecular mechanism of these phenomena.

Academic Significance and Societal Importance of the Research Achievements

NET形成は、感染症以外の疾患でも形成され、様々な疾患の病理に深く関与していることが相次いで報告されている。例えば、糖尿病では、NET形成が創傷治癒の阻害要因となっていること、また、自己免疫疾患では、過剰なNETに含まれる核酸やタンパク質の免疫系への暴露が、自己抗体産生を促進することが報告されている。本研究で明らかになった機構を標的としたNET形成の制御は種々の疾患の新しい治療療法の開発に繋がる可能性を示唆している。

Research Products

• [Journal Article] Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor (2021)
  • Author(s): Shibuya Takumi、Kamiyama Asami、Sawada Hirotaka、Kikuchi Kenta、Maruyama Mayu、Sawado Rie、Ikeda Naoki、Asano Kenichi、Kurotaki Daisuke、Tamura Tomohiko、Yoneda Atsuko、Imada Keisuke、Satoh Takashi、Akira Shizuo、Tanaka Masato、Yotsumoto Satoshi
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 663115-663115
  • DOI: 10.3389/fimmu.2021.663115
  • Peer Reviewed / Open Access
• [Journal Article] Oxidized Phospholipids and Neutrophil Elastase Coordinately Play Critical Roles in NET Formation (2021)
  • Author(s): Tokuhiro Takuto、Ishikawa Akane、Sato Haruka、Takita Shunya、Yoshikawa Ayuri、Anzai Ryoko、Sato Shinichi、Aoyagi Ryohei、Arita Makoto、Shibuya Takumi、Aratani Yasuaki、Shimizu Shigeomi、Tanaka Masato、Yotsumoto Satoshi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9 Pages: 718586-718586
  • DOI: 10.3389/fcell.2021.718586
  • Peer Reviewed / Open Access
• [Journal Article] Garcinielliptone G from Garcinia subelliptica Induces Apoptosis in Acute Leukemia Cells (2021)
  • Author(s): Yun YoungSook、Shioura Mariko、Hitotsuyanagi Yukio、Yotsumoto Satoshi、Takahashi Yuji、Aoyagi Yutaka、Kinoshita Takeshi、Takeya Koichi、Inoue Hideshi
  • Journal Title: Molecules Volume: 26 Issue: 9 Pages: 2422-2422
  • DOI: 10.3390/molecules26092422
  • Peer Reviewed / Open Access
• [Journal Article] Frontline Science:?Conversion of neutrophils into atypical Ly6G + SiglecF + immune cells with neurosupportive potential in olfactory neuroepithelium (2020)
  • Author(s): Ogawa Kei、Asano Kenichi、Yotsumoto Satoshi、Yamane Tsuyoshi、Arita Makoto、Hayashi Yoshihiro、Harada Hironori、Makino‐Okamura Chieko、Fukuyama Hidehiro、Kondo Kenji、Yamasoba Tatsuya、Tanaka Masato
  • Journal Title: Journal of Leukocyte Biology Volume: 109 Issue: 3 Pages: 481-496
  • DOI: 10.1002/jlb.1hi0620-190rr
  • Peer Reviewed
• [Journal Article] Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis. (2019)
  • Author(s): K. Dodo, E*. Kuboki*, T Shimizu* (*equally contributed first author), R. Imamura, M. Magarisawa, M. Takahashi, T. Tokuhiro, S. Yasumoto, K. Asano, S. Nakao, N. Terayama, T.Suda, M. Tanaka, M. Sodeoka.
  • Journal Title: ACS Med Chem Lett. Volume: 10 Issue: 9 Pages: 1272-1278
  • DOI: 10.1021/acsmedchemlett.9b00142
  • Peer Reviewed / Open Access
• [Presentation] 脂質酸化依存的ネトーシスの誘導機構 (2021)
  • Author(s): 四元聡志
  • Organizer: 第94回日本生化学会大会
  • Invited
• [Presentation] 新しい単球サブセットによる がん転移の促進とその機構 (2021)
  • Author(s): 四元聡志
  • Organizer: 第65回日本薬学会関東支部大会
  • Invited
• [Presentation] Myeloperoxidase-dependent lipid peroxidation plays a critical role in neutrophil extracellular trap formation (2019)
  • Author(s): Takuto Tokuhiro, Satoshi Yotsumoto, Haruka Sato, Sayuri Yoshikawa, Shunya Takita, Masato Tanaka、
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] ネトーシスにおける脂質酸化制御の分子機構 (2019)
  • Author(s): 四元聡志、田中 正人
  • Organizer: 日本薬学会第140年会
• [Book] 細胞死 (2019)
  • Author(s): 三浦 正幸、清水 重臣
  • Total Pages: 216
  • Publisher: 化学同人
  • ISBN: 9784759817317