Analysis of a mechanism of neutrophil extracellular trap (NET) fromation and a role of NETs in infectious and inflammatory diseases.

• Project/Area Number: 23591474
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kyoto University
• Principal Investigator: YAMASHITA KOUHEI 京都大学, 医学(系)研究科(研究院), 講師 (80402858)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 好中球細胞外トラップ / NADPH oxidase / 一重項酸素 / 血栓性微小血管障害 / 造血幹細胞移植 / 高尿酸血症 / 心血管障害 / 殺菌 / 好中球 / 細胞外トラップ / 血管内皮細胞障害 / 同種造血細胞移植 / IgG4関連疾患 / 微小血管障害 / 活性酸素 / 慢性肉芽腫症

Research Abstract

Neutrophil extracellular traps (NETs), a newly recognized extracellular killing mechanism by activated neutrophils, contribute to host defense, however, it is reported to be relevant to the pathogenesis of immunothrombosis and inflammatory/ autoimmune diseases by releasing potent hazarous mediators, such as anti-microbial peptides. In this study, we revealed three major findings as below; 1) Siglet oxygen, one of the reactive oxygen species produced by activated neutrophils, is essential for NET formation, 2) Serum NET levels predict thrombotic microangiopathy after allogeneic stem cell transplantaion (SCT), which is one of the critical complications of SCT. 3) Uric acid induces NADPH oxidase-independent NET formation, suggesting that NETs could be a missing link between serum uric acid elevation and cardiovascular diseases.

Research Products

• [Journal Article] Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation (2014)
  • Author(s): Arai Y, Nishinaka Y, Arai T, Morita M, Mizugishi K, Adachi S, Takaori-Kondo A, Watanabe T, Yamashita K
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Pages: 556-61
  • NAID: 40021104154
  • Peer Reviewed
• [Journal Article] 好中球の細胞外殺菌機構(NETs)-感染防御における役割と自己免疫・炎症病態への関与- (2014)
  • Author(s): 新井康之,山下浩平
  • Journal Title: 炎症と免疫 Volume: 22 Pages: 122-34
• [Journal Article] Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation. (2014)
  • Author(s): Arai Y, Nishinaka Y, Arai T, Morita M, Mizugishi K, Adachi S, Takaori-Kondo A, Watanabe T, Yamashita K.
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Issue: 2 Pages: 556-561
  • DOI: 10.1016/j.bbrc.2013.12.007
  • NAID: 40021104154
  • Peer Reviewed
• [Journal Article] CKIP-1 Is an Intrinsic Negative Regulator of T-Cell Activation through an Interaction with CARMA1. (2014)
  • Author(s): Sakamoto T, Kobayashi M, Tada K, Shinohara M, Io K, Nagata K, Iwai F, Takiuchi Y, Arai Y, Yamashita K, Shindo K, Kadowaki N, Koyanagi Y, Takaori-Kondo A
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: 1-11
  • DOI: 10.1371/journal.pone.0085762
  • Peer Reviewed
• [Journal Article] Serum neutrophil extracellular traps levels predict thrombotic microangiopathy after allogeneic stem cell transplantation (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A
  • Journal Title: Biol Blood Marrow Transpl Volume: 19 Pages: 1683-9
  • Peer Reviewed
• [Journal Article] Enhanced generation of reactive oxygen species by interferon-may have contributed to successful treatment of invasive pulmonary aspergillosis in a patient with chronic granulomatous disease (2013)
  • Author(s): Yamashita K, Miyoshi T, Arai Y, Mizugishi K, Takaori-Kondo A, Ueyama T
  • Journal Title: Int J Hematol Volume: 97 Pages: 505-10
  • Peer Reviewed
• [Journal Article] The implication of myelodysplastic syndrome-associated chromosomal abnormalities in the development of graft-versus-host disease (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Takaori-Kondo A, Chiba T, Watanabe T
  • Journal Title: Eur J Haematol Volume: 90 Pages: 525-30
  • Peer Reviewed
• [Journal Article] Familial Mediterranean fever mutations in a patient with recurrent episodes of acute respiratory distress syndrome (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Watanabe T, Kondo T, Kitano T, Kawabata H, Kadowaki N, Takaori-Kondo A
  • Journal Title: Clin Immunol Volume: 147 Pages: 58-60
  • Peer Reviewed
• [Journal Article] Toll-like receptor activation in basophils contributes to the development of IgG4-related disease (2013)
  • Author(s): Watanabe T, Yamashita K, Sakurai T, Kudo M, Shiokawa M, Uza N, Kodama Y, Uchida K, Okazaki K, Chiba T
  • Journal Title: J Gastroenterol Volume: 48 Pages: 247-53
  • NAID: 10031156310
  • Peer Reviewed
• [Journal Article] The implication of myelodysplastic syndrome-associated chromosomal abnormalities in the development of graft-versus-host disease. (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Takaori-Kondo A, Chiba T, Watanabe T.
  • Journal Title: Eur J Haematol Volume: 90 Issue: 6 Pages: 525-530
  • DOI: 10.1111/ejh.12100
  • Peer Reviewed / Open Access
• [Journal Article] Serum neutrophil extracellular traps levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A.
  • Journal Title: Biol Blood Marrow Transpl Volume: 19 Issue: 12 Pages: 1683-1689
  • DOI: 10.1016/j.bbmt.2013.09.005
  • Peer Reviewed
• [Journal Article] Toll-like receptor activation in basophils contributes to the development of IgG4-related disease. (2013)
  • Author(s): Watanabe T, Yamashita K, Sakurai T, et al
  • Journal Title: J Gastroenterol Volume: 48 Issue: 2 Pages: 247-253
  • DOI: 10.1007/s00535-012-0626-8
  • NAID: 10031156310
  • Peer Reviewed
• [Journal Article] Familial Mediterranean fever mutations in a patient with recurrent episodes of acute respiratory distress syndrome. (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Watanabe T, Kondo T, Kitano T, Kawabata H, Kadowaki N, Takaori-Kondo A.
  • Journal Title: Clin Immunol Volume: 147 Issue: 1 Pages: 58-60
  • DOI: 10.1016/j.clim.2013.02.016
  • Peer Reviewed
• [Journal Article] Enhanced generation of reactive oxygen species by interferon-gamma may have contributed to successful treatment of invasive pulmonary aspergillosis in a patient with chronic granulomatous disease. (2013)
  • Author(s): Yamashita K, Miyoshi T, Arai Y, Mizugishi K, Takaori-Kondo A, Ueyama T.
  • Journal Title: Int J Hematol Volume: 97 Issue: 4 Pages: 505-510
  • DOI: 10.1007/s12185-013-1315-y
  • Peer Reviewed
• [Journal Article] Differing impacts of pretransplant serum ferritin and c-reactive protein levels on the incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (2013)
  • Author(s): Sakamoto S, Kawabata H, Kanda J, Uchiyama T, Mizumoto C, Kondo T, Yamashita K, Ichinohe T, Ishikawa T, Kadowaki N, Takaori-Kondo A
  • Journal Title: Int J Hematol Volume: 97 Issue: 1 Pages: 109-116
  • DOI: 10.1007/s12185-012-1229-0
  • NAID: 10031144642
  • Peer Reviewed
• [Journal Article] Clinical value of (11)C-methionine PET/CT in patients with plasma cell malignancy: comparison with (18)F-FDG PET/CT (2013)
  • Author(s): Nakamoto Y, et al
  • Journal Title: Eur J Nucl Med Mol Imaging Volume: Vol.40、No.5 Issue: 5 Pages: 708-715
  • DOI: 10.1007/s00259-012-2333-3
  • Peer Reviewed
• [Journal Article] Activation of toll-like receptors and NOD-like receptors in involved in enhanced IgG4 responses in autoimmune pancreatitis (2012)
  • Author(s): Watanabe T, Yamashita K, Fujikawa S, Sakurai T, Kudo M, Shiokawa M, Kodama Y, Uchida K, Okazaki K, Chiba T
  • Journal Title: Arthritis Rheum Volume: 64 Pages: 914-24
  • Peer Reviewed
• [Journal Article] Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis. (2012)
  • Author(s): Watanabe T, Yamashita K, Fujikawa S, Sakurai T, Kudo M, Shiokawa M, Kodama Y, Uchida K, Okazaki K, Chiba T.
  • Journal Title: Arthritis Rheum Volume: 64 Pages: 914-924
  • Peer Reviewed
• [Journal Article] Singlet oxygen is essential for neutrophil extracellular trap formation (2011)
  • Author(s): Nishinaka Y, Arai T, Adachi S, Takaori-Kondo A, Yamashita K
  • Journal Title: Biochem Biophys Res Commun Volume: 413 Pages: 75-9
  • Peer Reviewed
• [Journal Article] Singlet oxygen is essential for neutrophil extracellular trap formation. (2011)
  • Author(s): Nishinaka Y, Arai T, Adachi S, Takaori-Kondo A, Yamashita K.
  • Journal Title: Biochem Biophys Res Commun Volume: 413 Pages: 75-79
  • Peer Reviewed
• [Presentation] Uric Acid Induces NADPH Oxidase-Independent Neutrophil Extracellular Trap Formation (2013)
  • Author(s): Arai Y, Nishinaka Y, Arai T, Mizugishi K, Adachi S, Takaori-Kondo A, Yamashita K
  • Organizer: 55th Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2013-12-10
• [Presentation] Plasmacytoid dendritic cells activated by neutrophil extracellular traps contribute to the pathogenesis of IgG4-related disease (2013)
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Takaori-Kondo A
  • Organizer: Annual European Congress of Rheumatology EULAR 2013
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2013-06-13
• [Presentation] Serum Neutrophil Extracellular Traps (NETs) Are a Potential Predictive Marker for Thrombotic Microangiopathy (TMA) After Allogeneic Stem Cell Transplantation (2012)
  • Author(s): Arai Y, Sakamoto S, Yamashita K, Mizugishi K, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A
  • Organizer: 54th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2012-12-08
• [Presentation] A novel role of uric acid in neutrophil extracellular trap formation (2012)
  • Author(s): Nishinaka Y, Arai T, Morita M, Arai Y, Mizugishi K, Adachi S, Takaori-Kondo A, Yamashita K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-20
• [Presentation] 高濃度尿酸によるNADPH oxidase非依存性NETosisの誘導 (2012)
  • Author(s): 西中瑶子,森田真紀子,荒井俊之,山下浩平,足立壯一
  • Organizer: 第21回日本Cell Death学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-07-28
• [Presentation] Serum Neutrophil Extracellular Traps (NETs) Are a Potential Predictive Marker for Thrombotic Microangiopathy (TMA) After Allogeneic Stem Cell Transplantation. (2012)
  • Author(s): Arai Y, Sakamoto S, Yamashita K, Mizugishi K, Kitano T, Kondo T, Kawabata H, Kadowaki N, Takaori-Kondo A.
  • Organizer: 54th Annual Meeting of the American Society of Hematology
  • Place of Presentation: 米国Atlanta, Convention Center
• [Presentation] ARDSを繰り返し発症した，MEFV遺伝子変異を有するMDS/MPNの一例． (2012)
  • Author(s): 新井康之, 山下浩平, 水岸貴代美, 近藤忠一, 北野俊行, 川端浩, 高折晃史．
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都、国立京都国際会館
• [Presentation] A novel role of uric acid in neutrophil extracellular trap formation. (2012)
  • Author(s): Nishinaka Y, Arai T, Morita M, Arai Y, Mizugishi K, Adachi S, Takaori-Kondo A, Yamashita K.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都、国立京都国際会館
• [Presentation] 高濃度尿酸によるNADPH oxidase非依存性NETosisの誘導． (2012)
  • Author(s): 西中 瑶子，森田 真紀子，荒井 俊之，山下 浩平，足立 壯一．
  • Organizer: 第21回日本Cell Death学会学術集会
  • Place of Presentation: 名古屋、名古屋大学医学部付属病院中央診療棟3階講堂
• [Presentation] リツキシマブ投与後の遅発性好中球減少症に関する検討． (2012)
  • Author(s): 新井康之, 山下浩平, 近藤忠一, 高折晃史．
  • Organizer: 第82回日本感染症学会中日本地方会学術集会．
  • Place of Presentation: 福岡、アクロス福岡
• [Presentation] Singlet oxygen is essential for neutrophil extracellular trap formation (2011)
  • Author(s): Nishinaka Y, Morita M, Arai T, Adachi S, Takaori-Kondo A, Yamashita K
  • Organizer: The 53^<rd> ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-12-12
• [Presentation] Singlet oxygen is essential for neutrophil extracellular trap formation (2011)
  • Author(s): Yamashita K, Nishinaka Y, Arai T, adachi S, Takaori-Kondo A
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] Singlet oxygen is essential for neutrophil extracellular trap formation. (2011)
  • Author(s): Yamashita K, Nishinaka Y, Arai T, Adachi S, Takaori-Kondo A.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋市、名古屋国際会議場
• [Presentation] Singlet oxygen is essential for neutrophil extracellular trap formation. (2011)
  • Author(s): Nishinaka Y, Morita M, Arai T, Adachi S, Takaori-Kondo A, Yamashita K.
  • Organizer: 53rd ASH Annual Meeting and Exposition
  • Place of Presentation: 米国San Diego, Convention Center
• [Presentation] Plasmacytoid dendritic cells activated by neutrophil extracellular traps contribute to the pathogenesis of IgG4-related disease.
  • Author(s): Arai Y, Yamashita K, Mizugishi K, Takaori-Kondo A.
  • Organizer: Annual European Congress of Rheumatology EULAR 2013.
  • Place of Presentation: Madrid, Spain
• [Presentation] 同種造血幹細胞移植後の低ガンマグロブリン血症に関する後方視的解析．
  • Author(s): 新井康之, 山下浩平, 近藤忠一, 北野俊行, 高折晃史．
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Uric Acid Induces NADPH Oxidase-Independent Neutrophil Extracellular Trap Formation.
  • Author(s): Arai Y, Nishinaka Y, Arai T, Mizugishi K, Adachi S, Takaori-Kondo A, Yamashita K.
  • Organizer: 55th Annual Meeting of the American Society of Hematology.
  • Place of Presentation: New Orleans, USA
• [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
  • URL: http://www.kuhp.kyoto-u.ac.jp/~hemonc/research/biophylaxis.html
• [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: http://www.kuhp.kyoto-u.ac.jp/~hemonc/research/biophylaxis.html