The mechanisms of eosinophil cell death-associated degranulation and their clinical implications

• Project/Area Number: 25460670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Akita University
• Principal Investigator: UEKI Shigeharu 秋田大学, 医学(系)研究科(研究院), 准教授 (60361234)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 好酸球 / アレルギー / ETosis / DNA traps / 好酸球性副鼻腔炎 / 好酸球性中耳炎 / 脱顆粒 / 細胞死 / 炎症 / アポトーシス

Outline of Final Research Achievements

Eosinophils have been considered end-stage effector cells involved in allergic inflammation through their release of cytotoxic granule proteins. Eosinophil cytolysis is an activated phenotype that has been previously observed in biological specimens from patients with disease, and deposition of free eosinophil granules is readily observed in the affected tissues or secretions from these patients. Using pathological specimen and blood-derived human eosinophils, we reported that activated eosinophils undergo a distinct programed pathway of rapid non-apoptotic cell death, extracellular trap cell death (ETosis). ETosis involves the cytolytic release of intact granules also in conjunction with filamentous chromatin structures (DNA traps). Further, we showed that ETosis-mediated DNA traps abundantly present in eosinophilic secretions from patients with eosinophilic chronic rhinosinusitis and contributed to increase their viscosity and chronic inflammation.

Research Products

• [Int'l Joint Research] Beth Israel Deaconess Medical Center(米国)
• [Int'l Joint Research]
• [Journal Article] Eosinophil extracellular trap cell death-derived DNA traps: Their presence in secretions and functional attributes. (2016)
  • Author(s): Ueki S, Konno Y, Takeda M, Moritoki Y, Hirokawa M, Matsuwaki Y, Honda K, Ohta N, Yamamoto S, Takagi Y, Wada A, Weller PF.
  • Journal Title: J Allergy Clin Immunol. Volume: 137 Issue: 1 Pages: 258-267
  • DOI: 10.1016/j.jaci.2015.04.041
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 好酸球の活性化-顆粒内蛋白の放出とその役割 (2015)
  • Author(s): 今野泰典，中村由夏，植木重治
  • Journal Title: 成人病と生活習慣病 Volume: 45 Pages: 821-826
• [Journal Article] Functional ana- lysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis. (2015)
  • Author(s): Konno, Y., Ueki, S., Takeda, M., Kobayashi, Y., Tamaki, M., Moritoki, Y., Oyamada, H., Itoga, M., Kayaba, H., Omokawa, A., Hirokawa, M.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0120386-e0120386
  • DOI: 10.1371/journal.pone.0120386
  • Peer Reviewed / Open Access
• [Journal Article] G-Protein-Coupled Estrogen Receptor Agonist Suppresses Airway Inflammation in a Mouse Model of Asthma through IL-10. (2015)
  • Author(s): Itoga, M., Konno, Y., Moritoki, Y., Saito, Y., Ito, W., Tamaki, M., Kobayashi, Y., Kayaba, H., Kikuchi, Y., Chihara, J., Takeda, M., Ueki, S., Hirokawa, M.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0123210-e0123210
  • DOI: 10.1371/journal.pone.0123210
  • Peer Reviewed / Open Access
• [Journal Article] プログラムされた細胞死：Extracellular trap cell death (ETosis) と病態 (2014)
  • Author(s): 植木重治, 今野泰典, 廣川誠
  • Journal Title: バイオメディカル Volume: 24 Pages: 26-30
• [Journal Article] Expression and functional roles of G-protein-coupled estrogen receptor (GPER) in human eosinophils. (2014)
  • Author(s): Tamaki M, Konno Y, Kobayashi Y, Takeda M, Itoga M, Moritoki Y, Oyamada H, Kayaba H, Chihara J, Ueki S.
  • Journal Title: Immunology Letters Volume: 160 Issue: 1 Pages: 72-78
  • DOI: 10.1016/j.imlet.2014.03.012
  • Peer Reviewed
• [Journal Article] The effect of pharmacological PI3Kγ inhibitor on eotaxin-induced human eosinophil functions. (2014)
  • Author(s): Saito, Y., Takeda, M., Nishikawa, J., Konno, Y., Tamaki, M., Itoga, M., Kobayashi, Y., Moritoki, Y., Ito, W., Chihara, J., Ueki, S.
  • Journal Title: Pulm Pharmacol Ther. Volume: 27 Issue: 2 Pages: 164-169
  • DOI: 10.1016/j.pupt.2013.11.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Eliciting Eosinophil CCR3 Expression by Synthetic Retinoids (2014)
  • Author(s): Ueki, S., Nishikawa, J., Konno, Y., Tamaki, M., Takeda, M., Moritoki, Y., Chihara, J.
  • Journal Title: Allergology International Volume: 63 Issue: Supplement.1 Pages: S67-S68
  • DOI: 10.2332/allergolint.13-LE-0641
  • NAID: 130004477226
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. (2013)
  • Author(s): Ueki S, Melo RC, Ghiran I, Spencer LA, Dvorak AM, Weller PF.
  • Journal Title: Blood Volume: 121 Issue: 11 Pages: 2074-83
  • DOI: 10.1182/blood-2012-05-432088
  • Peer Reviewed
• [Journal Article] Human eosinophils express functional CCR7. (2013)
  • Author(s): Akuthota P, Ueki S, Estanislau J, Weller PF.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 48 Issue: 6 Pages: 758-64
  • DOI: 10.1165/rcmb.2012-0499oc
  • Peer Reviewed
• [Journal Article] Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation. (2013)
  • Author(s): Yamamoto R, Ueki S, Moritoki Y, Kobayashi Y, Oyamada H, Konno Y, Tamaki M, Itoga M, Takeda M, Ito W, Chihara J.
  • Journal Title: Journal of Asthma Volume: 50 Issue: 8 Pages: 828-835
  • DOI: 10.3109/02770903.2013.816725
  • Peer Reviewed
• [Journal Article] Retinoic acids up-regulate functional eosinophil-driving receptor CCR3. (2013)
  • Author(s): Ueki S, Nishikawa J, Yamauchi Y, Konno Y, Tamaki M, Itoga M, Kobayashi Y, Takeda M, Moritoki Y, Ito W, Chihara J.
  • Journal Title: Allergy. Volume: 68 Issue: 7 Pages: 953-956
  • DOI: 10.1111/all.12175
  • Peer Reviewed
• [Presentation] 好酸球性副鼻腔炎・中耳炎の分泌液におけるDNA trapsの存在と役割 (2015)
  • Author(s): 植木重治，今野泰典，竹田正秀，中村由夏，嵯峨知生，面川 歩，守時由起，廣川 誠
  • Organizer: 第62回日本臨床検査医学会学術集会
  • Place of Presentation: 岐阜
  • Year and Date: 2015-11-19
• [Presentation] DNA trapsは好酸球性ムチンの粘性亢進に関与する (2015)
  • Author(s): 植木重治，今野泰典，竹田正秀，中村由夏，廣川 誠，松脇由典，太田伸男，本田耕平
  • Organizer: アレルギー・好酸球研究会2015
  • Place of Presentation: 東京
  • Year and Date: 2015-10-24
• [Presentation] Novel Cell death ETosis is a Therapeutic Target for Eosinophilic Disorders. (2015)
  • Author(s): Ueki S
  • Organizer: XXIV World Allergy Congress
  • Place of Presentation: Seoul
  • Year and Date: 2015-10-14
  • Int'l Joint Research / Invited
• [Presentation] 好酸球性ムチンの粘稠性に寄与するDNA traps (2015)
  • Author(s): 植木重治
  • Organizer: 第54回日本鼻科学会総会・学術講演会
  • Place of Presentation: 広島
  • Year and Date: 2015-10-01
  • Invited
• [Presentation] 気道粘液中のExtracellular DNA trapsを観察したアレルギー性気管支肺アスペルギルス症(ABPA)の一例 (2015)
  • Author(s): 植木重治，今野泰典，竹田正秀，面川 歩，嵯峨知生，守時由起，浅野真理子，奥田佑道，佐藤一洋，佐野正明，伊藤 宏，塩谷隆信，廣川 誠
  • Organizer: 第49回東北アレルギー懇話会
  • Place of Presentation: 秋田
  • Year and Date: 2015-07-04
• [Presentation] 分離好酸球のETosisを検出する簡便な実験法の確立 (2015)
  • Author(s): 植木重治，今野泰典，竹田正秀，守時由起，中村由夏，面川 歩，廣川 誠，Peter Weller
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-26
• [Presentation] 好酸球のETosisにより生じるDNA trapsは微生物を捕捉する (2015)
  • Author(s): 植木重治，今野泰典，守時由起，竹田正秀，山本志緒里，高木由里，和田 淳，面川 歩，廣川 誠，Peter Weller
  • Organizer: 第55回日本呼吸器学会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-17
• [Presentation] ヒト好酸球におけるエストロゲン膜受容体(GPER)の発現と機能 (2014)
  • Author(s): 植木重治，玉木真実，竹田正秀，今野泰典，小山田一，面川歩，守時由起，茆原順一，廣川誠
  • Organizer: 第61回日本臨床検査医学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-22 – 2014-11-25
• [Presentation] 好酸球のETosis:細胞死により獲得する新たな機能 (2014)
  • Author(s): 植木重治
  • Organizer: 第53回日本耳鼻科学会総会・学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 好酸球のETosisによる脱顆粒：電子顕微鏡による形態学的特徴 (2014)
  • Author(s): 今野泰典，植木重治，千田進介，玉木真実，守時由起，竹田正秀，廣川誠
  • Organizer: 第26回日本アレルギー学会春季臨床大会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-09 – 2014-05-11
• [Presentation] 好酸球Extracellular DNA trapsの機能的特性 (2014)
  • Author(s): 植木重治，今野泰典，玉木真実，竹田正秀，守時由起，廣川誠，Weller Peter
  • Organizer: 第26回日本アレルギー学会春季臨床大会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-09 – 2014-05-11
• [Presentation] 治療により気道粘液中Extracellular DNA trapsの減少を認めたアレルギー性気管支肺アスペルギルス症の一例 (2014)
  • Author(s): 菊池悠太，植木重治，今野泰典，玉木真実，竹田正秀，浅野真理子，佐藤一洋，佐野正明，伊藤宏，廣川誠
  • Organizer: 第26回日本アレルギー学会春季臨床大会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-09 – 2014-05-11
• [Presentation] 好酸球のExtracellular DNA trap cell deathにおける形態変化‐電子顕微鏡による検討 (2014)
  • Author(s): 植木重治，今野泰典，玉木真実，守時由起，竹田正秀，Rossana CN Melo，Peter F Weller
  • Organizer: 第54回日本呼吸器学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Trapping capacity and stability of eosinophil extracellular DNA nets. (2013)
  • Author(s): Ueki S, Melo RCN, Weller PF.
  • Organizer: 8th Biennial symposium of the international eosinophil society.
  • Place of Presentation: Oxford, UK
• [Presentation] Free secretion competent eosinophil granules are produced by eosinophil extracellular DNA trap cell death (2013)
  • Author(s): Ueki S，Chihara J，Melo RCM，Ghiran I，Spencer LA，Weller PF.
  • Organizer: 第53回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
• [Presentation] ヒト好酸球におけるリンパ節ホーミング受容体CCR7の機能解析 (2013)
  • Author(s): 植木重治，Akuthota P，Weller PF
  • Organizer: 第63回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京
• [Presentation] ETosis「Extracellular DNA」
  • Author(s): 植木重治
  • Organizer: 第24回バイオメディカルフォーラム
  • Place of Presentation: 東京
  • Invited
• [Book] 免疫・アレルギー疾患イラストレイテッド.田中良哉（編）好酸球増多症･好酸球増多症候群 (2013)
  • Author(s): 植木重治, 茆原順一
  • Total Pages: 359
  • Publisher: 羊土社
• [Remarks] ｜ニュース｜秋田大学 大学院医学系研究科・医学部
  • URL: http://www.med.akita-u.ac.jp/news/20150623.html
• [Remarks] 蓄のう症:悪化原因解明 治療薬開発に期待 秋田大など /秋田
  • URL: http://mainichi.jp/auth/guide.php?url=%2Farticles%2F20150618%2Fddl%2Fk05%2F040%2F166000c
• [Remarks] なおらない蓄膿症、網状ＤＮＡがカギ 秋田大院・植木准教授ら解明
  • URL: http://b.hatena.ne.jp/entry/apital.asahi.com/article/news/2015061900022.html
• [Remarks] MDLinx
  • URL: http://www.mdlinx.com/allergy-immunology/news-article.cfm/4664395