Analysis for the mechanism by which IL-5 production is reinforced by miRNA in exosome from mast cells

• Project/Area Number: 19K17687
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nippon Medical School (2021-2022); Nihon University (2019-2020)
• Principal Investigator: Toyoshima Shota 日本医科大学, 医学部, 助教 (30807954)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: マスト細胞 / 細胞外小胞 / microRNA / 2型自然リンパ球 / アレルギー炎症 / ヒトマスト細胞 / サイトカイン産生 / タンパク質メチル化 / IL-5 / PRMT5 / 2型サイトカイン / エクソソーム

Outline of Research at the Start

細胞はエクソソームと呼ばれる直径30-100 nmの小胞を分泌することが知られている。そこに内包されるタンパク質やマイクロRNAがアレルギー疾患の発症に関与することが示唆されている。そこで本研究計画では、アレルギーの責任細胞であるマスト細胞から遊離されるエクソソーム中マイクロRNAが、どのような機序で2型自然リンパ球からのIL5産生を増強し、喘息の増悪化に関与するかを明らかにする。

Outline of Final Research Achievements

The present study demonstrated that miR103a-3p was highly expressed in exosomes released by mast cells. These exosomes reduced the expression levels of PRMT5 in group 2 innate lymphoid cells and skewed methylated GATA3 to demethylated GATA3 in ILC2, leading to enhancement of IL-5 produciton, contributing to eosinophilia, from ILC2. Together, these might suggest that miR103a-3p in exosoomes from mast cells contributed to the exacerbation of eosinophil-mediated allergic inflammation.

Academic Significance and Societal Importance of the Research Achievements

エクソソームに内包されるタンパク質やmiRNAは細胞間相互作用に重要な役割を果たすことがよく知られているが, マスト細胞が遊離するエクソソーム中のmiRNAの役割に関して, 初めて明らかにした. その結果, アトピー性皮膚炎などのアレルギー疾患を遷延化させるメカニズムの一端を明らかにできた.

Research Products

• [Journal Article] Neuro-allergology: Mast cell-nerve cross-talk (2022)
  • Author(s): Toyoshima S, Okayama Y
  • Journal Title: Allergology International Volume: 71 Issue: 3 Pages: 288-293
  • DOI: 10.1016/j.alit.2022.04.002
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Higher PGD2 production by synovial mast cells from rheumatoid arthritis patients compared with osteoarthritis patients via miR-199a-3p/prostaglandin synthetase 2 axis (2021)
  • Author(s): Mishima S, Kashiwakura J, Toyoshima S, Sasaki-Sakamoto T, Sano Y, Nakanishi K, Matsumoto K, Okayama Y
  • Journal Title: Sci Rep Volume: In press Issue: 1
  • DOI: 10.1038/s41598-021-84963-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells (2021)
  • Author(s): Toyoshima S, Sakamoto-Sasaki T, Kurosawa Y, Hayama K, Matsuda A, Watanabe Y, Terui T, Gon Y, Matsumoto K, Okayama Y
  • Journal Title: J Allergy Clin Immunol Volume: In press Issue: 5 Pages: 1878-1891
  • DOI: 10.1016/j.jaci.2021.01.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Higher PGD2 production by synovial mast cells from rheumatoid arthritis patients compared with osteoarthritis patients via miR199a-3p/Cyclooxygenase 2 axis (2021)
  • Author(s): Shota Toyoshima, Shintaro Mishima, Jun-ichi Kashiwakura, Tomomi Sasaki-Sakamoto, Yutaka Sano1, Kazuyoshi Nakanishi, Kenji Matsumoto, Yoshimichi Okayama
  • Organizer: 第70回日本アレルギー学会
• [Presentation] miR103a-3p in extracellular vesicles from FcεRI-aggregated 1 human mast cells enhances IL-5 production by group 2 innate lymphoid cells (2021)
  • Author(s): Shota Toyoshima, Tomomi Sakamoto-Sasaki, Yusuke Kurosawa, Koremasa Hayama, Akira Matsuda, Yasuo Watanabe, Tadashi Terui, Yasuhiro Gon, Kenji Matsumoto, Yoshimichi Okayama
  • Organizer: 第70回日本アレルギー学会
• [Presentation] 豊島翔太, 坂本朋美, 黒澤雄介, 葉山惟大, 松田彰, 渡部保男, 照井正, 權寧博, 松本健治, 岡山吉道 (2021)
  • Author(s): IgE依存性に活性化したマスト細胞が遊離する細胞外小胞中のmiR103a-3pは, 2型自然リンパ球からのIL-5産生を増強させる.
  • Organizer: 第49回日本臨床免疫学会
• [Presentation] Shota Toyoshima, Tomomi Sakamoto-Sasaki, Yusuke Kurosawa, Koremasa Hayama, Akira Matsuda, Yasuo Watanabe, Tadashi Terui, Yasuhiro Gon, Kenji Matsumoto, Yoshimichi Okayama (2021)
  • Author(s): miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells
  • Organizer: APSR2021
• [Presentation] miR103a-3p in extracellular vesicles derived from human mast cells following aggregation of FcεRI enhances IL-5 production from IL-33-stimulated type2 innate lymphoid cells via PRMT5 (2020)
  • Author(s): Shota Toyoshima, Tomomi Sakamoto-Sasaki, Yusuke Kurosawa, Koremasa Hayama, Akira Matsuda, Y Watanabe, Tadashi Terui, Yasuhiro Gon, Kenji Matsumoto, Yoshimichi Okayama
  • Organizer: JSA/WAO Joint Congress 2020
  • Int'l Joint Research
• [Presentation] miR103a-3p in extracellular vesicles derived from human mast cells following aggregation of FceRI enhances IL-5 production from IL-33-stimulated type2 innate lymphoid cells (ILC2) via silencing protein arginine methyltransferase. (2019)
  • Author(s): Toyoshima S, Sakamoto-Sasaki T, Matsumoto K, Okayama Y
  • Organizer: WAC (World Allergy Congress) 2019
  • Int'l Joint Research
• [Presentation] miRNA103a-3p in extracellur vesicles derived from anti-IgE Ab activated human mast cells enhances IL-5 production in ILC2 in the presence of IL-33. (2019)
  • Author(s): Shota Toyoshima, Tomomi Sasaki-Sakamoto, Yusuke Kurosawa, Yasuhiro Gon, Chisei Ra, Kenji Matsumoto, Yoshimichi Okayama.
  • Organizer: 第48回日本免疫学会
• [Presentation] 抗IgE抗体によって活性化したマスト細胞が遊離する細胞外小胞中のmiR103a-3pは, 2型自然リンパ球からのIL-5産生を増強させる. (2019)
  • Author(s): 豊島翔太, 坂本朋美, 黒澤雄介, 權寧博, 羅智靖, 松本健治, 岡山吉道
  • Organizer: 2019年アレルギー・好酸球研究会
• [Presentation] Exosomal miRNA derived from anti-IgE activated human mast cells enhances IL-5 production in ILC2 in the presence of IL-33. (2019)
  • Author(s): Shota Toyoshima, Tomomi Sasaki-Sakamoto, Yasuhiro Gon, Chisei Ra, Kenji Matsumoto, Yoshimichi Okayama
  • Organizer: 第68回日本アレルギー学会
• [Remarks] アレルギー炎症を増悪・遷延化させ、その炎症を全身に拡げるメカニズムの解明
  • URL: https://www.med.nihon-u.ac.jp/up_pdf/20210222140231.pdf