The role of neutrophil extracellular traps in the pathogenesis of immunological, inflammatory, or thrombotic diseases

• Project/Area Number: 15K09499
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: Yamashita Kouhei 京都大学, 医学研究科, 准教授 (80402858)
• Research Collaborator: Mizugishi Kiyomi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 好中球細胞外トラップ / IgG4関連疾患 / 自己免疫性膵炎 / 不育症 / スフィンゴ脂質 / スフィンゴシンキナーゼ / 流産 / PAD阻害剤 / PAD4阻害剤 / 形質細胞様樹状細胞 / 1型インターフェロン / IL-33

Outline of Final Research Achievements

Neutrophil extracellular traps (NETs), a novel extracellular killing mechanism of neutrophils, are profoundly involved in the pathogenesis of immunological, inflammatory, or thrombotic diseases, due to harmful histons and anti-microbial proteins extracellularly released, although NETs contribute to host defense against microbial pathogens. In this study, we reported that NETs play an important role in the pathogenesis of autoimmune pancreatitis, one of the phenotypes of IgG4 disease, and pregnancy loss due to the disrupt of feto-maternal tolerance by abnormal sphingolipid metabolisms, such as defect of sphingosine kinases.

Academic Significance and Societal Importance of the Research Achievements

本研究では、稀少疾患である自己免疫性膵炎の病態にNETsが関与することを明らかにし、その治療としてNETs産生系制御の可能性を示した。また、母児間の免疫寛容の破綻による流産マウスモデルの解析から、NETsがエフェクターとなり流産を引き起こすことや、NETs産生を抑制するPAD4阻害剤の投与により流産の割合が劇的に低減することを示した。これらは、これまで主に獲得免疫系の異常と考えられた疾患の病態に自然免疫系、特に好中球の異常が深く関わることを示した、学術的に独自性の高い研究成果である。
また、原因不明の不育症の病態の一端を明らかにし、その新規治療の可能性を示したことは極めて社会的意義が大きい。

Research Products

• [Journal Article] Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase-deficient mice on 129Sv/C57BL/6 background. (2017)
  • Author(s): Mizugishi K and Yamashita K.
  • Journal Title: FASEB J. Volume: 31 Issue: 12 Pages: 5577-5591
  • DOI: 10.1096/fj.201700399rr
  • Peer Reviewed
• [Journal Article] Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells. (2017)
  • Author(s): Watanabe T, Yamashita K, Arai Y, Minaga K, Kamata K, Nagai T, Komeda Y, Takenaka M, Hagiwara S, Ida H, Sakurai T, Nishida N, Strober W, Kudo M.
  • Journal Title: J Immunol Volume: 印刷中 Issue: 10 Pages: 3886-3896
  • DOI: 10.4049/jimmunol.1700060
  • Peer Reviewed / Open Access
• [Journal Article] 自己免疫性膵炎の診断について 診断基準の変遷と診断の現状 (2015)
  • Author(s): 内田 一茂, 岡崎 和一
  • Journal Title: 日本臨床免疫学会雑誌 Volume: 38 Issue: 7 Pages: 127-134
  • DOI: 10.4049/jimmunol.1500971
  • NAID: 130005089220
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phagocytosis by human monocytes is required for the secretion of presepsin. (2015)
  • Author(s): Arai Y, Mizugishi K, Nonomura K, Naito K, Takaori-Kondo A, Yamashita K.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 21 Issue: 8 Pages: 564-569
  • DOI: 10.1016/j.jiac.2015.04.011
  • Peer Reviewed
• [Journal Article] Enhancement of neutrophil autophagy by an IVIG preparation against multi-drug-resistant bacteria as well as drug sensitive strains. (2015)
  • Author(s): Itoh H, Matsuo H, Kitamura N, Yamamoto S, Higuchi T, Takematsu H, Kamikubo Y, Kondo T, Yamashita K, Sasada M, Takaori-Kondo A, Adachi S.
  • Journal Title: Journal of Leukocyte Biology Volume: 98 Issue: 1 Pages: 107-117
  • DOI: 10.1189/jlb.4a0813-422rrr
  • Peer Reviewed / Open Access
• [Remarks] 京都大学大学院医学研究科 血液・腫瘍内科学 生体防御研究室
  • URL: https://kuhp.kyoto-u.ac.jp/~hemonc/research/biophylaxis.html