Analysis of cytokines involved in induction of inflammation associated with disruption of epithelial barrier

• Project/Area Number: 18H02847
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Hiroshima University (2020); The University of Tokyo (2018-2019)
• Principal Investigator: Nakae Susumu 広島大学, 統合生命科学研究科(生), 教授 (60450409)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: アレルギー / 喘息 / サイトカイン / マウス疾患モデル / IL-33

Outline of Final Research Achievements

Barrier function of epithelial cells is important for prevention of the invasion of foreign antigens in healthy persons. When the barrier function becomes dysfunctional, antigens invade the body, following by induction of local inflammation. One of the factors is protease derived from house dust mites, pollen, and so on. When mice were inhaled with proteases, necrosis of airway epithelial cells are induced, resulting in induction of eosinophilic airway inflammation. We identified cytokines such as IL-17B, IL-31 and IL-36, which were expressed during this inflammation. Using these gene-deficient mice, we found that IL-17B, IL-31 and IL-36 were involved in development of protease-induced airway inflammation.

Academic Significance and Societal Importance of the Research Achievements

プロテアーゼの吸入による気道炎症は、細胞死が誘導された上皮細胞から放出されるIL-33が起点となって炎症が起こる。過去の我々の研究成果を含む多くのマウスを用いた基礎的研究成果を踏まえて、現在、欧米の製薬会社では喘息患者などの治療薬として、IL-33中和抗体の製薬化が進められている。本研究での成果、「IL-33依存的な気道炎症に関わる遺伝子IL-17B、IL-31、IL-36の同定とその機能解析」は、喘息の発症のメカニズムの全容解明に貢献できる学術的な意義に加え、これらサイトカインの中和抗体などは、新規抗体治療薬の開発といったアレルギーの予防・治療法の開発への貢献といった社会的な意義を持つ。

Research Products

• [Int'l Joint Research] Yonsei University College of Medicine/Kyungpook National University(韓国)
• [Int'l Joint Research] NIH(米国)
• [Journal Article] Interleukin-33 and thymic stromal lymphopoietin, but not interleukin-25, are crucial for development of airway eosinophilia induced by chitin (2021)
  • Author(s): Arae Ken、Ikutani Masashi、Horiguchi Kotaro、Yamaguchi Sachiko、Okada Youji、Sugiyama Hiroki、Orimo Keisuke、Morita Hideaki、Suto Hajime、Okumura Ko、Taguchi Haruhiko、Matsumoto Kenji、Saito Hirohisa、Sudo Katsuko、Nakae Susumu
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 5913-5913
  • DOI: 10.1038/s41598-021-85277-4
  • Peer Reviewed / Open Access
• [Journal Article] Experimental mouse models of ragweed- and papain-induced allergic conjunctivitis. (2021)
  • Author(s): Matsuda A, Hirakata T, Asada Y
  • Journal Title: Method in Molecular Biology Volume: 2223 Pages: 133-149
  • DOI: 10.1007/978-1-0716-1001-5_10
  • ISBN: 9781071610008, 9781071610015
  • Peer Reviewed
• [Journal Article] Innate IL-17A enhances IL-33-independent skin eosinophilia and IgE response on subcutaneouspapain sensitization (2021)
  • Author(s): Kamijo S, Hara M, Suzuki M, Nakae S, Ogawa H, Okumura K, Takai T
  • Journal Title: J Invest Dermatol Volume: 141 Issue: 1 Pages: 105-113.e14
  • DOI: 10.1016/j.jid.2020.05.088
  • Peer Reviewed
• [Journal Article] Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia (2020)
  • Author(s): Unno Hirotoshi、Arae Ken、Matsuda Akira、Ikutani Masashi、Tamari Masato、Motomura Kenichiro、Toyama Sumika、Suto Hajime、Okumura Ko、Matsuda Akio、Morita Hideaki、Sudo Katsuko、Saito Hirohisa、Matsumoto Kenji、Nakae Susumu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 533 Issue: 3 Pages: 493-500
  • DOI: 10.1016/j.bbrc.2020.09.046
  • Peer Reviewed / Open Access
• [Journal Article] A mouse model of asthma‐chronic obstructive pulmonary disease overlap induced by intratracheal papain (2020)
  • Author(s): Fukuda Kensuke、Matsuzaki Hirotaka、Mikami Yu、Makita Kosuke、Miyakawa Kazuko、Miyashita Naoya、Hosoki Keisuke、Ishii Takashi、Noguchi Satoshi、Urushiyama Hirokazu、Horie Masafumi、Mitani Akihisa、Yamauchi Yasuhiro、Shimura Eri、Nakae Susumu、Saito Akira、Nagase Takahide、Hiraishi Yoshihisa
  • Journal Title: Allergy Volume: 76 Issue: 1 Pages: 390-394
  • DOI: 10.1111/all.14528
  • Peer Reviewed
• [Journal Article] Exophilin-5 regulates allergic airway inflammation by controlling IL-33-mediated Th2 responses (2020)
  • Author(s): Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Ray Ishizaki, Eri Kobayashi, Miho Kihara, Takaya Abe, Jun-ichi Miyazaki, Masafumi Horie, Akira Saito, Hirohisa Saito, Susumu Nakae, Tetsuro Izumi
  • Journal Title: Journal of Clinical Investigation Volume: - Issue: 7 Pages: 3919-3935
  • DOI: 10.1172/jci127839
  • NAID: 40022605127
  • Peer Reviewed / Open Access
• [Journal Article] TSLP is a negative regulator of RANKL-induced osteoclastogenesis. (2020)
  • Author(s): Ohno, T., Nakamura, T., Nakae, S., Morita, H., Matsumoto, K., Takeda, K., Okumura, K., and Azuma, T.
  • Journal Title: Biochem. Biophsy. Res. Commun. Volume: 530 Issue: 3 Pages: 508-512
  • DOI: 10.1016/j.bbrc.2020.05.055
  • Peer Reviewed
• [Journal Article] Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid (2019)
  • Author(s): Morita H, Kubo T, Ruckert B, Ravindran A, Soyka M, Rinaldi A, Sugita K, Wawrzyniak M, Wawrzyniak P, Motomura K, Tamari M, Orimo K, Okada N, Arae K, Saito K, Altunbulakli C, Castro-Giner F, Tan G, Neumann A, Sudo K, O’Mahony L, Honda K, Nakae S, Saito H, Mjösberg J, Nilsson G, Matsumoto K, Akdis M, Akdis CA
  • Journal Title: J Allergy Clin Immunol. Volume: in press Issue: 6 Pages: 2190-2201
  • DOI: 10.1016/j.jaci.2018.12.1018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium (2019)
  • Author(s): Kobayashi Tetsuro、Voisin Benjamin、Kim Do Young、Kennedy Elizabeth A.、Jo Jay-Hyun、Shih Han-Yu、Truong Amanda、Doebel Thomas、Sakamoto Keiko、Cui Chang-Yi、Schlessinger David、Moro Kazuyo、Nakae Susumu、Horiuchi Keisuke、Zhu Jinfang、Leonard Warren J.、Kong Heidi H.、Nagao Keisuke
  • Journal Title: Cell Volume: 176 Issue: 5 Pages: 982-997.e16
  • DOI: 10.1016/j.cell.2018.12.031
  • Peer Reviewed
• [Journal Article] Cyclooxygenase inhibition in mice heightens adaptive‐ and innate‐type responses against inhaled protease allergen and IL ‐33 (2019)
  • Author(s): Maruyama Natsuko、Takai Toshiro、Kamijo Seiji、Suchiva Punyada、Ohba Mai、Takeshige Tomohito、Suzuki Mayu、Hara Mutsuko、Matsuno Kei、Harada Sonoko、Harada Norihiro、Nakae Susumu、Sudo Katsuko、Okuno Toshiaki、Yokomizo Takehiko、Ogawa Hideoki、Okumura Ko、Ikeda Shigaku
  • Journal Title: Allergy Volume: 印刷中 Issue: 11 Pages: 2237-2240
  • DOI: 10.1111/all.13831
  • Peer Reviewed / Open Access
• [Journal Article] Innate Lymphoid Cells in the Induction of Obesity (2019)
  • Author(s): Sasaki T, Moro K, Kubota T, Kubota N, Kato T, Ohno H, Nakae S, Saito H, Koyasu S.
  • Journal Title: Cell Rep Volume: 28 Issue: 1 Pages: 202-217
  • DOI: 10.1016/j.celrep.2019.06.016
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous IL-33 exerts CD8+ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model. (2019)
  • Author(s): Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 2019 Issue: 2 Pages: 331-336
  • DOI: 10.1016/j.bbrc.2019.08.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice (2019)
  • Author(s): Yoshizaki T, Itoh S, Yamaguchi S, Numata T, Nambu A, Kimura N, Suto H, Okumura K, Sudo K, Yamaguchi A, Nakae S.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 17067-17067
  • DOI: 10.1038/s41598-019-53633-0
  • Peer Reviewed / Open Access
• [Journal Article] IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity (2018)
  • Author(s): Takamori Ayako、Nambu Aya、Sato Keiko、Yamaguchi Sachiko、Matsuda Kenshiro、Numata Takafumi、Sugawara Takeru、Yoshizaki Takamichi、Arae Ken、Morita Hideaki、Matsumoto Kenji、Sudo Katsuko、Okumura Ko、Kitaura Jiro、Matsuda Hiroshi、Nakae Susumu
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 6639-6639
  • DOI: 10.1038/s41598-018-25094-4
  • Peer Reviewed / Open Access
• [Journal Article] IL-36α is involved in hapten-specific T-cell induction, but not local inflammation, during contact hypersensitivity (2018)
  • Author(s): Numata Takafumi、Yoshizaki Takamichi、Yamaguchi Sachiko、Shimura Eri、Iwakura Yoichiro、Harada Kazutoshi、Sudo Katsuko、Tsuboi Ryoji、Nakae Susumu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 506 Issue: 3 Pages: 429-436
  • DOI: 10.1016/j.bbrc.2018.10.104
  • Peer Reviewed / Open Access
• [Journal Article] The roles of IL-17C in T cell-dependent and -independent inflammatory diseases (2018)
  • Author(s): Yamaguchi Sachiko、Nambu Aya、Numata Takafumi、Yoshizaki Takamichi、Narushima Seiko、Shimura Eri、Hiraishi Yoshihisa、Arae Ken、Morita Hideaki、Matsumoto Kenji、Hisatome Ichiro、Sudo Katsuko、Nakae Susumu
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15750-15750
  • DOI: 10.1038/s41598-018-34054-x
  • Peer Reviewed / Open Access
• [Journal Article] IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation (2018)
  • Author(s): Hiraishi Yoshihisa、Yamaguchi Sachiko、Yoshizaki Takamichi、Nambu Aya、Shimura Eri、Takamori Ayako、Narushima Seiko、Nakanishi Wakako、Asada Yosuke、Numata Takafumi、Suzukawa Maho、Yamauchi Yasuhiro、Matsuda Akira、Arae Ken、Morita Hideaki、Hoshino Tomoaki、Suto Hajime、Okumura Ko、Matsumoto Kenji、Nakae Susumu
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 18052-18052
  • DOI: 10.1038/s41598-018-36440-x
  • Peer Reviewed / Open Access
• [Presentation] Analysis of the pathogenic mechanism of asthma-like airway inflammation induced by chitin, an environmental microparticle (2020)
  • Author(s): Susumu Nakae, Ken Arae
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Role of IL-25 in development of contact dermatitis (2019)
  • Author(s): 中江 進
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] アレルギー性気道炎症のメカニズム up-to-date (2018)
  • Author(s): 中江 進
  • Organizer: 第67回日本アレルギー学会学術大会