Elucidation of the mechanism of eosinophil degranulation associated with cell death and its application to the evaluation of disease(Fostering Joint International Research)

• Project/Area Number: 15KK0329
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Akita University
• Principal Investigator: Ueki Shigeharu 秋田大学, 医学系研究科, 准教授 (60361234)
• Project Period (FY): 2016 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
• Keywords: 好酸球 / ETosis / 脱顆粒 / ヒストン / DNA / 細胞外トラップ / アレルギー / 細胞死 / 免疫 / 炎症

Outline of Final Research Achievements

In this international collaborative study, the mechanisms that determine eosinophil cell death (ETosis) in allergic diseases and the relationship between ETosis and pathogenesis in actual inflammatory tissues were elucidated. In allergic bronchopulmonary aspergillosis, eosinophil ETosis occurs at the site of inflammation and the mechanism of pathogen-induced ETosis was clarified. In addition, the presence of ETosis in eosinophilic otitis media and eosinophilic rhinosinusitis was also demonstrated. Charcot-Leiden crystals, galectin-10, chemokines, and extracellular vesicles were shown to be possible markers of allergic disease. These results have been reported in international journals and may provide the basis for future therapeutic strategies.

Academic Significance and Societal Importance of the Research Achievements

アレルギー疾患は頻度が高く増加傾向にある。なかでも難治性の好酸球性炎症疾患は医療費でも大きな割合を占め、世界的な問題になっている。本研究結果は、種々の難治性疾患のメカニズムを好酸球の細胞生物学的側面から明らかにしたものである。既存の概念にはなかった好酸球の細胞死という新しい視点から病態を理解することで、将来的な疾患モニタリングや治療に向けた道筋となる研究である。成果は複数の論文として当該分野のトップジャーナルを含む定評のある国際誌に掲載され、国内・国際学会の招請講演、依頼総説などを多く受けており、学術的な反響も大きかった。

Research Products

• [Int'l Joint Research] ハーバード大学(米国) (2017)
• [Journal Article] Galectin‐10, the protein that forms Charcot‐Leyden crystals, is not stored in granules but resides in the peripheral cytoplasm of human eosinophils (2020)
  • Author(s): Melo Rossana C. N.、Wang Haibin、Silva Thiago P.、Imoto Yoshimasa、Fujieda Shigeharu、Fukuchi Mineyo、Miyabe Yui、Hirokawa Makoto、Ueki Shigeharu、Weller Peter F.
  • Journal Title: Journal of Leukocyte Biology Volume: - Issue: 1 Pages: 139-149
  • DOI: 10.1002/jlb.3ab0220-311r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Critical role of CCL4 in eosinophil recruitment into the airway (2019)
  • Author(s): Kobayashi Yoshiki、Konno Yasunori、Kanda Akira、Yamada Yoshiyuki、Yasuba Hirotaka、Sakata Yoshiko、Fukuchi Mineyo、Tomoda Koichi、Iwai Hiroshi、Ueki Shigeharu
  • Journal Title: Clinical & Experimental Allergy Volume: - Issue: 6 Pages: 853-860
  • DOI: 10.1111/cea.13382
  • Peer Reviewed / Open Access
• [Journal Article] Eotaxin-3 as a Plasma Biomarker for Mucosal Eosinophil Infiltration in Chronic Rhinosinusitis (2019)
  • Author(s): Yamada Takechiyo、Miyabe Yui、Ueki Shigeharu、Fujieda Shigeharu、Tokunaga Takahiro、Sakashita Masafumi、Kato Yukinori、Ninomiya Takahiro、Kawasaki Yohei、Suzuki Shinsuke、Saito Hidekazu
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 74-74
  • DOI: 10.3389/fimmu.2019.00074
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of CD16-negative selection vs. MACSxpress system for isolation of blood eosinophils (2019)
  • Author(s): Fukuchi Mineyo、Ueki Shigeharu、Saito Hidekazu、Miyabe Yui、Konno Yasunori、Omokawa Ayumi、Saga Tomoo、Moritoki Yuki、Takeda Masahide、Yamada Takechiyo、Hirokawa Makoto
  • Journal Title: Allergology International Volume: 68 Issue: Supplement.1 Pages: S11-S13
  • DOI: 10.1016/j.alit.2019.04.005
  • NAID: 130007709782
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Severe Eosinophilic Disorders: Mechanisms and Clinical Management (2019)
  • Author(s): Akuthota Praveen、Neves Josiane S.、Ueki Shigeharu
  • Journal Title: Frontiers in Immunology Volume: 10
  • DOI: 10.3389/fimmu.2019.02118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eosinophilic Cholecystitis Occurred in a Patient With Refractory Eosinophilic Airway Inflammation: A Case Report (2019)
  • Author(s): Kuwahara Toshiaki、Kobayashi Yoshiki、Yun Yasutaka、Kanda Akira、Asako Mikiya、Ueki Shigeharu、Iwai Hiroshi
  • Journal Title: Allergy & Rhinology Volume: 10 Pages: 1177-1177
  • DOI: 10.1177/2152656719869607
  • Peer Reviewed / Open Access
• [Journal Article] Charcot-Leyden Crystals in Eosinophilic Inflammation: Active Cytolysis Leads to Crystal Formation (2019)
  • Author(s): Shigeharu Ueki, Yui Miyabe, Yohei Yamamoto, Mineyo Fukuchi, Makoto Hirokawa, Lisa A. Spencer, Peter F. Weller
  • Journal Title: Curr. Allergy Asthma Rep Volume: 19 Issue: 8 Pages: 38-38
  • DOI: 10.1007/s11882-019-0868-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eosinophil Extracellular Traps and Inflammatory Pathologies?Untangling the Web! (2018)
  • Author(s): Mukherjee Manali、Lacy Paige、Ueki Shigeharu
  • Journal Title: Frontiers in Immunology Volume: 9
  • DOI: 10.3389/fimmu.2018.02763
  • Peer Reviewed / Open Access
• [Journal Article] Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcγR-Expressing Mice (2018)
  • Author(s): Moritoki Y, Tsuneyama K, Nakamura Y, Kikuchi K, Shiota A, Ohsugi Y, Lian ZX, Zhang W, Yang GX, Ueki S, Takeda M, Omokawa A, Saga T, Saga A, Watanabe D, Miura M, Ueno Y, Leung PSC, Tanaka A, Gershwin ME, Hirokawa M.
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 2534-2534
  • DOI: 10.3389/fimmu.2018.02534
  • NAID: 120006937682
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model (2018)
  • Author(s): Yamada M, Kagaya M, Noguchi N, Ueki S, Hasunuma N, Osada SI, Manabe M.
  • Journal Title: J Dermatol Sci Volume: 92 Issue: 2 Pages: 134-142
  • DOI: 10.1016/j.jdermsci.2018.08.009
  • Peer Reviewed
• [Journal Article] Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death (2018)
  • Author(s): Ueki Shigeharu、Tokunaga Takahiro、Melo Rossana C. N.、Saito Hidekazu、Honda Kohei、Fukuchi Mineyo、Konno Yasunori、Takeda Masahide、Yamamoto Yohei、Hirokawa Makoto、Fujieda Shigeharu、Spencer Lisa A.、Weller Peter F.
  • Journal Title: Blood Volume: 132 Issue: 20 Pages: 2183-2187
  • DOI: 10.1182/blood-2018-04-842260
  • Peer Reviewed / Open Access
• [Journal Article] ICAM-1 upregulation is not required for retinoic acid-induced human eosinophil survival (2018)
  • Author(s): Ueki Shigeharu、Nishikawa Junko、Fukuchi Mineyo、Konno Yasunori、Takeda Masahide、Moritoki Yuki、Chihara Junichi、Omokawa Ayumi、Saga Tomoo、Hirokawa Makoto
  • Journal Title: Immunology Letters Volume: 196 Pages: 68-73
  • DOI: 10.1016/j.imlet.2018.01.013
  • Peer Reviewed / Open Access
• [Journal Article] Eosinophils release extracellular DNA traps in response to Aspergillus fumigatus (2018)
  • Author(s): Muniz Valdirene S.、Silva Juliana C.、Braga Yasmim A.V.、Melo Rossana C.N.、Ueki Shigeharu、Takeda Masahide、Hebisawa Akira、Asano Koichiro、Figueiredo Rodrigo T.、Neves Josiane S.
  • Journal Title: Journal of Allergy & Clinical Immunology Volume: 141 Issue: 2 Pages: 571-585.e7
  • DOI: 10.1016/j.jaci.2017.07.048
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lytic eosinophils produce extracellular DNA traps as well as free eosinophil granules (2018)
  • Author(s): Persson Carl、Ueki Shigeharu
  • Journal Title: J Allergy Clin Immunol Volume: 141 Issue: 3 Pages: 1164-1164
  • DOI: 10.1016/j.jaci.2017.05.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ETosis-derived DNA trap production in middle ear effusion is a common feature of eosinophilic otitis media (2018)
  • Author(s): Ohta N, et al
  • Journal Title: Allergology International Volume: 67 Issue: 3 Pages: 414-416
  • DOI: 10.1016/j.alit.2017.11.007
  • NAID: 130007420530
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Mucus plugging in allergic bronchopulmonary aspergillosis: Implication of the eosinophil DNA traps (2018)
  • Author(s): Omokawa Ayumi、Ueki Shigeharu、Kikuchi Yuta、Takeda Masahide、Asano Mariko、Sato Kazuhiro、Sano Masaaki、Ito Hiroshi、Hirokawa Makoto
  • Journal Title: Allergology International Volume: 67 Issue: 2 Pages: 280-282
  • DOI: 10.1016/j.alit.2017.08.002
  • NAID: 130006721874
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] アレルギー・好酸球性炎症の病態解明 (2017)
  • Author(s): 植木重治
  • Journal Title: Akita J Med Volume: 44 Pages: 11-17
  • NAID: 120006344054
  • Peer Reviewed
• [Journal Article] 好中球と好酸球のExtracellular trap cell death (2017)
  • Author(s): 植木重治，今野泰典，廣川 誠
  • Journal Title: 分子呼吸器病 Volume: 21 Pages: 12-15
• [Journal Article] 好酸球の新しい細胞死：ETosis (2017)
  • Author(s): 竹田正秀，植木重治, 廣川誠
  • Journal Title: アレルギー・免疫 Volume: 24 Pages: 48-53
• [Journal Article] Eosinophilic Otitis Media: the Aftermath of Eosinophil Extracellular Trap Cell Death. (2017)
  • Author(s): Ueki S, Ohta N, et al
  • Journal Title: Curr Allergy Asthma Rep Volume: 17 Issue: 5 Pages: 33-37
  • DOI: 10.1007/s11882-017-0702-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 好酸球の運命からみたECRSの病態 (2019)
  • Author(s): 植木重治
  • Organizer: 第37回日本耳鼻咽喉科免疫アレルギー学会
  • Invited
• [Presentation] 管腔内好酸球増多をきたす疾患群と好酸球の運命 (2019)
  • Author(s): 植木重治
  • Organizer: 第59回日本呼吸器学会学術講演会
  • Invited
• [Presentation] 組織における好酸球活性化の評価―細胞崩壊（cytolysis/ETosis）の免疫染色による検出 (2019)
  • Author(s): 福地峰世，植木重治，上出庸介，宮部 結，今野泰典，竹田正秀，面川 歩，嵯峨知生，守時由起，谷口正実，廣川 誠
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] Charcot-Leyden crystal formation is mediated through eosinophil ETosis (2019)
  • Author(s): Fukuchi, M., Ueki, S., Takeda, M., Miyabe, Y., Konno, Y., Yamamoto, Y., Omokawa, A., Saga, T., Hirokawa, M., Melo, R.C.N., Weller, P.F.
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] 細胞死を起点とする好酸球性炎症 (2019)
  • Author(s): 植木重治
  • Organizer: 第68回日本アレルギー学会学術大会
  • Invited
• [Presentation] 好酸球活性化に着目した炎症評価の課題 (2019)
  • Author(s): 植木重治
  • Organizer: 第68回日本アレルギー学会学術大会
  • Invited
• [Presentation] 真菌と上気道炎症性疾患 (2019)
  • Author(s): 山田武千代，齋藤秀和，宮部 結，植木重治
  • Organizer: 第68回日本アレルギー学会学術大会
  • Invited
• [Presentation] 好酸球ETosisに着目したシャルコー・ライデン結晶の病理学的検討 (2019)
  • Author(s): 齋藤秀和，植木重治，福地峰世，徳永貴広，今野泰典，山本洋平，宮部 結，山田武千代，廣川 誠
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] in vitroにおけるシャルコー・ライデン結晶の形成機構 (2019)
  • Author(s): 竹田正秀，植木重治，福地峰世，宮部 結，面川 歩，嵯峨知生，守時由起，佐藤一洋，佐野正明，中山勝敏，廣川 誠
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 著明な組織内シャルコー・ライデン結晶を認めた好酸球増多症候群患者 (2019)
  • Author(s): 福地峰世，植木重治，山本洋平，奈良美保，今野泰典，面川 歩，嵯峨知生，守時由起，大森泰文，高橋直人，廣川 誠
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 慢性肉芽腫症患者における好中球と好酸球のETosis (2019)
  • Author(s): 植木重治，福地峰世，矢野道広，宮部 結，村長 萌，面川 歩，嵯峨亜希子，嵯峨知生，守時由起，高橋 勉，廣川 誠
  • Organizer: 第1回日本アレルギー学会東北地方会
• [Presentation] 好酸球の行く末と好酸球性気道疾患の病態 (2019)
  • Author(s): 植木重治
  • Organizer: 第82回日本呼吸器学会 日本結核病学会 九州支部春季学術講演会
  • Invited
• [Presentation] Eosinophil Extracellular Traps(EETs):好酸球の新しい機能 (2019)
  • Author(s): 植木重治
  • Organizer: 第6回総合アレルギー講習会
  • Invited
• [Presentation] Eosinophil ETosis and Extracellular Chromatin Traps: A New Look at Eosinophilic Inflammation (2019)
  • Author(s): Ueki, S., Weller, P
  • Organizer: 11th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research / Invited
• [Presentation] How to visualize ETosis-derived eosinophil extracellular traps (2019)
  • Author(s): Ueki, S., Fukuchi, M., Omokawa, A., Saga, T., Miyabe, Y., Takeda, M., Saito, H., Moritoki, Y., Yamada, T., Hirokawa, M., Melo, R., Weller, P
  • Organizer: 11th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research / Invited
• [Presentation] First Ultrastructural Demonstration of Galectin-10 in Resting and Activated Human Eosinophils (2019)
  • Author(s): Melo, R., Wang, H., Ueki, S. Weller, P.
  • Organizer: 11th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research
• [Presentation] Detection of Eosinophil Cytolytic Degranulation in Paraffin-Embedded Tissue (2019)
  • Author(s): Fukuchi, M., Ueki, S., Tan, N., Kamide, Y., Omokawa, A., Saga, T., Saito, H., Yamada, T., Moritoki, Y., Taniguchi, M., Hirokawa, M
  • Organizer: 11th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research
• [Presentation] Aspergillus Fumigatusによる好酸球ETosisの誘導機構 (2018)
  • Author(s): 植木重治，Josiane Naves，竹田正秀，福地峰世，今野泰典，蛇澤 晶，浅野浩一郎，廣川 誠
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] アレルギー性気管支肺アスペルギルス症の粘液栓における好酸球Extracellular traps (2018)
  • Author(s): 竹田正秀，植木重治，福地峰世，今野泰典，面川 歩，嵯峨知生，嵯峨亜希子，守時由起，廣川 誠，蛇澤 晶，浅野浩一郎
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 管腔内好酸球増多 (luminal eosinophilia) をきたす疾患群とETosis (2018)
  • Author(s): 植木重治
  • Organizer: 第67回日本アレルギー学会学術大会
  • Invited
• [Presentation] 好酸球性中耳炎におけるeosinophil extracellular DNA trap cell death(EETosis) (2018)
  • Author(s): 太田伸男，植木重治，長舩大士，鈴木立俊，鈴木祐輔，高梨芳崇，藤枝重治
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] アレルギー性気管支炎肺アスペルギルス症の粘液栓への好酸球ETosis の関与 (2018)
  • Author(s): 竹田正秀，植木重治，Neves Josiane，福地峰世，今野泰典，佐藤一洋，佐野正明，廣川 誠，蛇澤 晶，浅野浩一郎
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] 好酸球増多を伴ったIgG4関連鼻副鼻腔炎の1例 (2018)
  • Author(s): 桑原敏彰，小林良樹，神田 晃，尾崎吉郎，植木重治，村田英之，朝子幹也，岩井 大
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] ECRS 鼻茸組織中の活性化好酸球はMIP-1βを発現する (2018)
  • Author(s): 尹 泰貴，小林良樹，Dan Bui Van，朝子幹也，植木重治，神田 晃，岩井 大
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] 20分で末梢血から好酸球を分離するMACSxpressの性能評価 (2018)
  • Author(s): 福地峰世，植木重治，斎藤秀和，面川 歩，嵯峨亜希子，嵯峨知生，山田武千代， 廣川 誠
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] 好酸球のETosisによるシャルコー・ライデン結晶の形成 (2018)
  • Author(s): 植木重治，竹田正秀，面川 歩，嵯峨知生，守時由起，鎌田由美子，廣川 誠
  • Organizer: 第65回日本臨床検査医学会学術集会
• [Presentation] 注目されている免疫細胞・メディエーター 顆粒球(好中球・好酸球・好塩基球) (2018)
  • Author(s): 植木重治
  • Organizer: 第5回総合アレルギー講習会
  • Invited
• [Presentation] MACSxpressにより高純度分離した好酸球の機能評価 (2018)
  • Author(s): 植木重治，福地峰世，齋藤秀和，竹田正秀，面川 歩，嵯峨亜希子，嵯峨知生，山田武千代，廣川 誠
  • Organizer: アレルギー・好酸球研究会2018
• [Presentation] PI3K/MAPK blockcade inhibits eosinophil extracellular trap cell death (2017)
  • Author(s): Ueki, S., Konno, Y., Omokawa, A., Saga, T., Takeda, M., Moritoki, Y., Hirokawa, M.
  • Organizer: 10th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research
• [Presentation] Eosinophils and Aspergillus fumigatus infection: a DNA trap release story (2017)
  • Author(s): Muniz, VS., Silva, JC., Braga, YAV., Melo, RCN., Ueki, S., Takeda, M., Hebisawa, A., Asano, K., Figueiredo, RT., Neves, JS.
  • Organizer: 10th Biennial Symposium of the International Eosinophil Society
  • Int'l Joint Research
• [Presentation] Eosinophil extracellular traps are abundant in the bronchial mucus plugs of patients with ABPA (2017)
  • Author(s): Fukuchi, M., Ueki, S., Takeda, M., Omokawa, A., Saga, T., Hebisawa, A., Asano, K., Neves, J., Hirokawa, M.
  • Organizer: 29th World Congress of World Association of Societies of Pathology and Laboratory Medicine
  • Int'l Joint Research
• [Presentation] ABPA患者の粘液栓におけるextracellular traps(ETs)の証明 (2017)
  • Author(s): 竹田正秀, 植木重治, 福地峰世, 面川歩, 嵯峨知生, 蛇澤晶, 浅野浩一郎, 廣川誠
  • Organizer: アレルギー・好酸球研究会2017
• [Presentation] 活性化したヒト好酸球から産生される細胞外小胞の特徴 (2017)
  • Author(s): 植木重治，竹田正秀，面川歩，嵯峨知生，廣川誠
  • Organizer: 第64回日本臨床検査医学会学術集会
• [Presentation] ヒト好酸球から産生されるextracellular microvesicles (2017)
  • Author(s): 植木重治，竹田正秀，中村由夏，丹 典子，廣川 誠， Akuthota P, Rossana CNM
  • Organizer: 第66回日本アレルギー学会学術大会
• [Remarks] アレルギー・好酸球性炎症の研究
  • URL: http://www.med.akita-u.ac.jp/~gimclm/research.html
• [Remarks] 細胞の自爆で体内に結晶ができる？
  • URL: https://academist-cf.com/journal/?p=8810