Pathological analysis of failure of collaboration between enteric neuron and immunity

• Project/Area Number: 18K07898
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Chiba University
• Principal Investigator: FUJIMURA LISA 千葉大学, バイオメディカル研究センター, 助教 (30376363)
• Co-Investigator(Kenkyū-buntansha): 坂本 明美 千葉大学, バイオメディカル研究センター, 准教授 (90359597)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腸管神経 / 好酸球 / IL5 / 腸炎 / 腸管免疫 / IgA

Outline of Final Research Achievements

We analyzed relation of enteric neurons (EN) and intestinal barrier using Ncx KO mice in which EN were increased. We demonstrated that eosinophils (Eo) increased in lamina propria (LP) of Ncx KO mice small intestine (SI) compared to those of WT mice. Expression of IL5 was higher in the intestinal tissues from Ncx KO than that from WT.
In order to examine whether IL5 is responsible for increased number of Eo in Ncx KO mice LP, we generated IL5 KO mice in Ncx KO background. FACS analysis revealed that mature Eo in LP was decreased in IL5/Ncx double KO mice compared to those of Ncx KO mice. As a result, the total Eo was decreased in double KO mice. These data indicated that high amount of IL5 expression in SI is responsible for mature Eo generation in Ncx KO mice. To elucidate that EN could products IL5, Immunohistology revealed that EN express IL5. We are currently investigating the mechanism of IL5 production from EN and biological significance of increased number of Eo in Ncx KO mice.

Academic Significance and Societal Importance of the Research Achievements

非常に高い防御機能をもつ腸管では、上皮系・内分泌系・免疫系・神経系・腸内細菌叢が相互作用を行い恒常性を維持している。それらのバランスが崩れると、腸炎などの機能異常が起こると考えられている。近年、粘膜に存在する神経系が免疫系細胞と解剖学的に非常に近接していること、それらが相互作用を行っていて、その破綻は炎症やアレルギーの原因であると報告されているが、ごく少数である。また、近年わが国で増加傾向にある潰瘍性大腸炎やクローン病などの難治性腸疾患の発症や病態は、多大なストレスと関連があるといわれており、神経系-免疫系相互作用の解明とその破綻による腸炎の病態解明における本研究は、非常に意義がある。

Research Products

• [Journal Article] Deletion of Eqtn in mice reduces male fertility and sperm-egg adhesion (2018)
  • Author(s): Ito Chizuru、Yamatoya Kenji、Yoshida Keiichi、Fujimura Lisa、Sugiyama Hajime、Suganami Akiko、Tamura Yutaka、Hatano Masahiko、Miyado Kenji、Toshimori Kiyotaka
  • Journal Title: Reproduction Volume: 156 Issue: 6 Pages: 579-590
  • DOI: 10.1530/rep-18-0394
  • Peer Reviewed / Open Access
• [Journal Article] Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells (2018)
  • Author(s): Takashi Ogasawara,Yuko Kohashi,Jun Ikari,Toshibumi Taniguchi,Nobuhide Tsuruoka,Haruko Watanabe-Takano,Lisa Fujimura,Akemi Sakamoto,Masahiko Hatano,Hirokuni Hirata,Yasutsugu Fukushima,Takeshi Fukuda,Kazuhiro Kurasawa,Koichiro Tatsumi,Takeshi Tokuhisa,Masafumi Arima
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 750-750
  • DOI: 10.3389/fimmu.2018.00750
  • Peer Reviewed / Open Access
• [Journal Article] Development of Noninvasive In Vivo Approach to Assess Vascular Permeability in Inflammation Using Fluorescence Imaging. (2017)
  • Author(s): Shimazui T, Nakada TA, Fujimura L, Sakamoto A, Hatano M, Oda S.
  • Journal Title: Shock. Volume: - Issue: 6 Pages: 1-1
  • DOI: 10.1097/shk.0000000000001075
  • Peer Reviewed / Open Access
• [Journal Article] Blocking Liver Autophagy Accelerates Apoptosis and Mitochondrial Injury in Hepatocytes and Reduces Time to Mortality in a Murine Sepsis Model. (2017)
  • Author(s): Oami T, Watanabe E, Hatano M, Teratake Y, Fujimura L, Sakamoto A, Ito C, Toshimori K, Swanson PE, Oda S.
  • Journal Title: Shock. Volume: - Issue: 4 Pages: 427-434
  • DOI: 10.1097/shk.0000000000001040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Roles of enteric neuron in eosinophil induction (2019)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Takashi Fumita, Masahiko Hatano
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] 腸管炎症における制御性T細胞の役割とオートファジーの関与 (2019)
  • Author(s): 中嶋利典、坂本明美、藤村理紗、清宮航、文田貴志、大森智瑛、幡野雅彦
  • Organizer: 第42回日本分子生物学会総会
• [Presentation] Ncx KOマウスを用いたプロポリスの腸管バリア機能改善に及ぼす効果の検討 (2019)
  • Author(s): 清宮航、藤村理紗、坂本明美、中嶋利典、文田貴志、幡野雅彦
  • Organizer: 第42回日本分子生物学会総会
• [Presentation] Analysis of the frequency and function of regulatory T-cell using human blood samples in biliary atresia. (2019)
  • Author(s): Satoru Oita, Takeshi Saito, Akemi Sakamoto, Keita Terui, Shugo Komatsu, Kazuaki Harada, Yoshitaka Shinno, Lisa Fujimura, Masahiko Hatano, Hideo Yoshida
  • Organizer: The Pacific Association of Pediatric Surgeons 52nd Annual Meeting
  • Int'l Joint Research
• [Presentation] Roles of enteric neurons in gut mucosal immunity (2018)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Masahiko Hatano
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 胆道閉鎖症の病態形成における制御性T細胞の意義 (2018)
  • Author(s): 笈田 諭, 齋藤 武, 坂本 明美, 照井 慶太, 中田 光政, 小松 秀吾, 原田 和明, 秦 佳孝, 勝海 大輔, 古金 遼也, 藤村理紗, 幡野 雅彦, 吉田 英生
  • Organizer: 第45回日本胆道閉鎖症研究会