Elucidation of mechanisms how M2 macrophages induced by basophils dampen excess inflammation

• Project/Area Number: 18K15180
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Miyake Kensuke 東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (90814533)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 好塩基球 / M2マクロファージ / IL-4 / 死細胞 / IL-1α / 炎症抑制 / アレルギー / 免疫学 / 好中球 / アレルギー炎症 / マクロファージ

Outline of Final Research Achievements

Elucidation of the pathophysiology of chronic allergic inflammation is the urgent problem in developed countries. Especially, the mechanisms for the termination of allergic inflammation remains ill-defined. Our group previously identified that basophils contribute to the termination of allergic inflammation by inducing the differentiation of anti-inflammatory M2-like macrophages.In this study, we investigated the molecular mechanisms how basophils and anti-inflammatory M2 macrophages dampen excess allergic inflammation. We discovered that activated basophils release IL-4 and enhance the capacity of dead cell clearance in M2 macrophages, thus preventing the aggravation of allergic inflammation caused by dead cell-derived mediators, including IL-1α.

Academic Significance and Societal Importance of the Research Achievements

これまでのアレルギー研究では、アレルギー炎症の誘導機構に重点が置かれ、発症に関与する分子がアレルギー疾患の治療標的とされてきた。しかしながらこの治療法では、すでに発症したアレルギー炎症の治療には有効ではない可能性が高い。アレルギー炎症の終息機構が解明できれば、アレルギーが発症している最中であっても炎症を終息させアレルギー症状を改善できる画期的な治療法の開発が期待される。本研究により、好塩基球やM2マクロファージによるアレルギー炎症の終息機構の一端が解明された。この研究を応用すれば、アレルギーの新規治療法開発につながると考えられ、社会的・学術的に大きな意義を持つ研究である。

Research Products

• [Int'l Joint Research] CVPath Institute(米国)
• [Int'l Joint Research] University of Cape Town(南アフリカ)
• [Journal Article] Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting. (2020)
  • Author(s): Yang Y, Nagai S, Kang S, Xia Y, Kawano Y, Miyake K, Karasuyama H, Azuma M.
  • Journal Title: International Immunology Volume: - Issue: 8 Pages: 509-518
  • DOI: 10.1093/intimm/dxaa014
  • Peer Reviewed / Open Access
• [Journal Article] 【アレルギーのエフェクター細胞研究の進展】好塩基球 (2020)
  • Author(s): 三宅 健介, 吉川 宗一郎, 柴田 翔, 山西 吉典, 烏山 一.
  • Journal Title: 臨床免疫・アレルギー科 Volume: 73 Pages: 6-13
• [Journal Article] Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3?stimulated murine basophils (2019)
  • Author(s): Yoshikawa Soichiro、Oh-hora Masatsugu、Hashimoto Ryota、Nagao Toshihisa、Peters Louis、Egawa Mayumi、Ohta Takuya、Miyake Kensuke、Adachi Takahiro、Kawano Yohei、Yamanishi Yoshinori、Karasuyama Hajime
  • Journal Title: Science Signaling Volume: 12 Issue: 576
  • DOI: 10.1126/scisignal.aav2060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 好塩基球による、トロゴサイトーシスを介した新たな抗原提示メカニズム (2019)
  • Author(s): 三宅 健介, 烏山 一
  • Journal Title: 感染・炎症・免疫 Volume: 49 Pages: 61-64
• [Journal Article] Th2型免疫応答における好塩基球の役割 (2019)
  • Author(s): 三宅 健介、 吉川 宗一郎、 山西 吉典、烏山 一
  • Journal Title: 臨床免疫・アレルギー科 Volume: 71 Pages: 177-184
  • NAID: 40021798131
• [Journal Article] Histamine Released From Skin-Infiltrating Basophils but Not Mast Cells Is Crucial for Acquired Tick Resistance in Mice (2018)
  • Author(s): Tabakawa Yuya、Ohta Takuya、Yoshikawa Soichiro、Robinson Elisabeth J.、Yamaji Kayoko、Ishiwata Kenji、Kawano Yohei、Miyake Kensuke、Yamanishi Yoshinori、Ohtsu Hiroshi、Adachi Takahiro、Watanabe Naohiro、Kanuka Hirotaka、Karasuyama Hajime
  • Journal Title: Frontiers in Immunology Volume: 9
  • DOI: 10.3389/fimmu.2018.01540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] How do basophils contribute to Th2 cell differentiation and allergic responses? (2018)
  • Author(s): Karasuyama Hajime、Miyake Kensuke、Yoshikawa Soichiro、Kawano Yohei、Yamanishi Yoshinori
  • Journal Title: International Immunology Volume: 30 Issue: 9 Pages: 391-396
  • DOI: 10.1093/intimm/dxy026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Basophils trigger emphysema development in a murine model of COPD through IL-4?mediated generation of MMP-12?producing macrophages (2018)
  • Author(s): Shibata Sho、Miyake Kensuke、Tateishi Tomoya、Yoshikawa Soichiro、Yamanishi Yoshinori、Miyazaki Yasunari、Inase Naohiko、Karasuyama Hajime
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 51 Pages: 13057-13062
  • DOI: 10.1073/pnas.1813927115
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aggregation makes a protein allergenic at the challenge phase of basophil-mediated allergy in mice (2018)
  • Author(s): Nagao Toshihisa、Yamanishi Yoshinori、Miyake Kensuke、Teranishi Mio、Takahashi Saori、Yoshikawa Soichiro、Kawano Yohei、Karasuyama Hajime
  • Journal Title: International Immunology Volume: 31 Issue: 1 Pages: 41-49
  • DOI: 10.1093/intimm/dxy062
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 免疫学のABC(第8回) 顆粒球の作用と役割 (2018)
  • Author(s): 三宅 健介
  • Journal Title: 分子リウマチ治療 Volume: 11 Pages: 148-151
  • NAID: 40021650431
• [Journal Article] トロゴサイトーシスを介した好塩基球による抗原提示機構 (2018)
  • Author(s): 三宅 健介、 山西吉典、 烏山 一
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70 Pages: 623-630
  • NAID: 40021747556
• [Journal Article] Multifaceted roles of basophils in health and disease (2017)
  • Author(s): Karasuyama H, Miyake K, Yoshikawa S, Yamanishi Y
  • Journal Title: J Allergy Clin Immunol Volume: S0091-6749 Issue: 2 Pages: 31894-31898
  • DOI: 10.1016/j.jaci.2017.10.042
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 慢性閉塞性肺疾患(COPD)患者の肺組織に好塩基球が浸潤している (2019)
  • Author(s): 柴田 翔, 立石 知也, 小林 正嗣, 大久保 憲一, 明石 巧, 三宅 健介, 山西 吉典, 烏山 一, 宮崎 泰成
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 好塩基球は炎症抑制型のM2マクロファージを誘導することで、アレルギー炎症の悪化を妨げる (2019)
  • Author(s): 三宅 健介
  • Organizer: 2019年先端モデル動物支援若手技術支援講習会
• [Presentation] Basophils promote the differentiation of monocytes into M2-like macrophages which dampen IL-1α-mediated aggravation of allergic inflammation (2019)
  • Author(s): Miyake K, Yoshikawa S, Yamanishi Y, Karasuyama H.
  • Organizer: 17th IUIS 2019 (International Congress of Immunology)
  • Int'l Joint Research
• [Presentation] Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3-stimulated basophils (2019)
  • Author(s): Yoshikawa S, Oh-hora M, Hashimoto R, Miyake K, Adachi T, Kawano Y, Yamanish Y, Kamiya A, Karasuyama H
  • Organizer: 17th IUIS 2019 (International Congress of Immunology)
  • Int'l Joint Research
• [Presentation] Monocyte-derived M2-like macrophages induced by activated basophils dampen IL-1α-mediated aggravation of allergic inflammation (2019)
  • Author(s): Miyake K, Yoshikawa S, Yamanishi Y, Karasuyama H
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Identification of immature-type basophils that are distinguishable from mature ones in terms of surface phenotype and activation property (2019)
  • Author(s): Ito J, Miyake K, Shichino S, Yamanishi Y, Karasuyama H
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Basophil-derived IL-4 promotes disease progression in a hapten-elicited murine model of atopic dermatitis (2019)
  • Author(s): Mogi K, Takahashi K, Miyake K, Yoshikawa S, Karasuyama H, Yamanishi Y
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Basophils promote monocyte differentiation to M2-like macrophages that display enhanced capacity of allergen clearance. (2018)
  • Author(s): Kensuke Miyake、 Ayako Fukui、 Soichiro Yoshikawa、 Yoshinori Yamanishi、 Hajime Karasuyama
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Aggregation makes a protein allergenic at the challenge phase of basophil-mediated allergy in mice. (2018)
  • Author(s): Toshihisa Nagao、 Yoshinori Yamanishi、 Kensuke Miyake、 Mio Teranishi、 Soichiro Yoshikawa、 Yohei Kawano、 Hajime Karasuyama
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Histamine Released From Skin-Infiltrating Basophils but not mast cells is crucial for acquired tick resistance in mice. (2018)
  • Author(s): Soichiro Yoshikawa、 Yuya Tabakawa、 Takuya Ohta、 Kayoko Yamaji、 Kenji Ishiwata、 Yohei Kawano、Yoshinori Yamanishi,、Hiroshi Ohtsu、Takahiro Adachi、 Naohiro Watanabe、 Hirotaka Kanuka、 Hajime Karasuyama
  • Organizer: 第47回日本免疫学会学術集会