Analysis of molecular mechanisms of lipid peroxidation-dependent NET formation

2021 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

免疫学

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。