Elucidation of unknown function of mast cells in atopic dermatitis associated with food allergy

• Project/Area Number: 15K09784
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Juntendo University
• Principal Investigator: NAKANO Nobuhiro 順天堂大学, 医学(系)研究科(研究院), 助教 (30420839)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 食物アレルギー / マウスモデル / マスト細胞 / Notchシグナル / 転写調節因子 / 皮膚炎

Outline of Final Research Achievements

Intestinal mast cells are a major effector cells in food allergy. However, the functions and differentiation process of intestinal mast cells are largely unknown.
In this study, we found that the response of mast cells to TGF-β, which is an inducer of intestinal mast cell differentiation, is mediated by the transcription factor EHF. In addition, we showed that the signaling mediated by Notch receptors contributes to the differentiation of intestinal mast cells. Moreover, the study using a mouse model of food allergy demonstrated that symptoms associated with food allergy are alleviated by administration of a Notch signaling inhibitor to the mice.

Research Products

• [Journal Article] The CD300e molecule in mice is an immune-activating receptor (2018)
  • Author(s): Isobe M, Izawa K, Sugiuchi M, Sakanishi T, Kaitani A, Takamori A, Maehara A, Matsukawa T, Takahashi M, Yamanishi Y, Oki T, Uchida S, Uchida K, Ando T, Maeda K, Nakano N, Yagita H, Takai T, Ogawa H, Okumura K, Kitamura T, Kitaura J.
  • Journal Title: J Biol Chem Volume: 293 Pages: 3793-3805
  • DOI: 10.1074/jbc.ra117.000696
  • Peer Reviewed / Open Access
• [Journal Article] Role of the Ceramide-CD300f Interaction in Gram-Negative Bacterial Skin Infections (2018)
  • Author(s): Maehara A, Kaitani A, Izawa K, Shiba E, Nagamine M, Takamori A, Isobe M, Uchida S, Uchida K, Ando T, Keiko M, Nakano N, Voehringer D, Roers A, Shimizu T, Ogawa H, Okumura K, Kitamura T, Kitaura J.
  • Journal Title: J Invest Dermatol Volume: 138 Pages: 1221-1224
  • DOI: 10.1016/j.jid.2017.11.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of PU.1 in NFATc1 promoter function in osteoclast development (2017)
  • Author(s): Ishiyama K, Yashiro T, Nakano N, Kasakura K, Miura R, Hara M, Kawai F, Maeda K, Tamura N, Okumura K, Ogawa H, Takasaki Y, Nishiyama C
  • Journal Title: Allergol. Int. Volume: 64(3) Issue: 3 Pages: 241-247
  • DOI: 10.1016/j.alit.2015.01.006
  • NAID: 130005290298
  • Year and Date: 2017-12-11
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Disrupting ceramide-CD300f interaction prevents septic peritonitis by stimulating neutrophil recruitment (2017)
  • Author(s): Izawa K, Maehara A, Isobe M, Yasuda Y, Urai M, Hoshino Y, Ueno K, Matsukawa T, Takahashi M, Kaitani A, Shiba E, Takamori A, Uchida S, Uchida K, Maeda K, Nakano N, Yamanishi Y, Oki T, Voehringer D, Roers A, Nakae S, Ishikawa J, Kinjo Y, Shimizu T, Ogawa H, Okumura K, Kitamura T, Kitaura J
  • Journal Title: Sci Rep Volume: 7(1) Pages: 4298-4298
  • DOI: 10.1038/s41598-017-04647-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i>Clock</i>-dependent temporal regulation of IL-33/ST2-mediated mast cell response (2017)
  • Author(s): Kawauchi T, Ishimaru K, Nakamura Y, Nakano N, Hara M, Ogawa H, Okumura K, Shibata S, Nakao A
  • Journal Title: Allergol. Int. Volume: 印刷中 Issue: 3 Pages: 472-478
  • DOI: 10.1016/j.alit.2017.02.004
  • NAID: 130005858846
  • Peer Reviewed / Open Access
• [Journal Article] Ceramide-CD300f Binding Inhibits Lipopolysaccharide-induced Skin Inflammation (2017)
  • Author(s): Shiba E, Izawa K, Kaitani A, Isobe M, Maehara A, Uchida K, Maeda K, Nakano N, Ogawa H, Okumura K, Kitamura T, Shimizu T, Kitaura J
  • Journal Title: The Journal of biological chemistry Volume: 292 Pages: 2924-2932
  • DOI: 10.1074/jbc.m116.768366
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pharmacologic inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia. (2017)
  • Author(s): Honjo A, Nakano N, Yamazaki S, Hara M, Uchida K, Kitaura J, Nishiyama C, Yagita H, Ohtsuka Y, Ogawa H, Okumura K, Shimizu T
  • Journal Title: J Allergy Clin Immunol Volume: 139 Pages: 987-996
  • DOI: 10.1016/j.jaci.2016.05.046
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 腸管マスト細胞の分化と分布に対するNotchシグナルの役割と食物アレルギーへのNotchシグナルの関与 (2017)
  • Author(s): 中野信浩、本庄明日香、奥村康
  • Journal Title: 臨床免疫・アレルギー科 Volume: 67 Pages: 68-73
• [Journal Article] Role of PU.1 in MHC class II expression via CIITA transcription in plasmacytoid dendritic cells. (2016)
  • Author(s): Miura R, Kasakura K, Nakano N, Hara M, Maeda K, Okumura K, Ogawa H, Yashiro T, Nishiyama C
  • Journal Title: PloS one Volume: 11
  • DOI: 10.1371/journal.pone.0154094
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of IgE-mediated allergic reaction by pharmacologically targeting the circadian clock. (2016)
  • Author(s): Nakamura Y, Nakano N, Ishimaru K, Ando N, Katoh R, Suzuki-Inoue K, Koyanagki S, Ogawa H, Okumura K, Shibata S, Nakao A
  • Journal Title: Journal of allergy and clinical Immunology Volume: 137(4) Pages: 1226-1235
  • DOI: 10.1016/j.jaci.2015.08.052
  • NAID: 40020962856
  • Peer Reviewed / Open Access
• [Journal Article] Notch signaling enhances FcεRI-mediated cytokine production by mast cells through direct and indirect mechanisms (2015)
  • Author(s): Nakano, N., Nishiyama, C., Yagita, H., Hara, M., Motomura, Y., Kubo, M., Okumura, K., and Ogawa, H
  • Journal Title: The Journal of Immunology Volume: 194(9) Pages: 4535-44
  • DOI: 10.4049/jimmunol.1301850
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] he Transcription Factor Ehf Is Involved in TGF-β-Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells. (2015)
  • Author(s): Yamazaki S, Nakano N, Honjo A, Hara M, Maeda K, Nishiyama C, Kitaura J, Ohtsuka Y, Okumura K, Ogawa H, Shimizu T
  • Journal Title: J Immunol. Volume: 195(7) Pages: 3427-3425
  • DOI: 10.4049/jimmunol.1402856
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TGF-βによるマスト細胞のFcεRIおよびc-Kitの発現抑制 (2015)
  • Author(s): 中野信浩、山﨑 晋、奥村 康
  • Journal Title: 臨床免疫・アレルギー科 Volume: 64(5) Pages: 429-434
• [Presentation] Notchシグナルによってマスト細胞が獲得する抗原提示細胞様の形質 (2017)
  • Author(s): 中野信浩、西山千春、奥村康、小川 秀興
  • Organizer: 日本農芸化学会2017年度大会
  • Place of Presentation: 京都女子大学（京都府・京都市）
  • Year and Date: 2017-03-18
• [Presentation] Notchシグナルによってマスト細胞が獲得する抗原提示細胞様の形質 (2017)
  • Author(s): 中野 信浩、西山 千春、奥村 康、小川 秀興
  • Organizer: 日本農芸化学会2017年度大会
• [Presentation] 腸管マスト細胞の形質発現におけるNotchシグナルの寄与 (2017)
  • Author(s): 中野信浩、北浦次郎、西山千春、八木田秀雄、奥村康、小川秀興
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] Mast cells acquire intestinal antigen-presenting cell-like properties by Notch signaling (2017)
  • Author(s): Nobuhiro Nakano, Ko Okumura, Hideoki Ogawa
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Notch signaling contributes to the acquisition of an antigen-presenting cell-like phenotype in intestinal mast cells (2017)
  • Author(s): Nobuhiro Nakano, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 日本研究皮膚科学会 第42回年次学術大会・総会
• [Presentation] Notch signaling contributes to differentiation of mucosal mast cells and development of experimental food allergy (2016)
  • Author(s): Nobuhiro Nakano, Asuka Honjo, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 日本研究皮膚科学会 第41回年次学術大会・総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia (2016)
  • Author(s): NAKANO Nobuhiro, HONJO Asuka, YAMAZAKI Susumu, OHTSUKA Yoshikazu, YAGITA Hideo, SHIMIZU Toshiaki, OKUMURA Ko, OGAWA Hideoki
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県・宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] Notchシグナル阻害による食物アレルギーの症状の軽減 (2016)
  • Author(s): 中野信浩、本庄明日香、西山千春、大塚宜一、清水俊明、奥村 康、小川 秀興
  • Organizer: 日本農芸化学会2016年度大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-03-27
• [Presentation] TGF-β-induced suppression of mast cell functions is mediated by the transcription factor Ehf (2015)
  • Author(s): Nobuhiro Nakano, Susumu Yamazaki, Chiharu Nishiyama, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 日本研究皮膚科学会 第40回年次学術大会・総会
  • Place of Presentation: 岡山コンベンションセンター（岡山県・岡山市）
  • Year and Date: 2015-12-11
• [Presentation] Notch signaling enhances mast cell cytokine production through direct and indirect mechanisms (2015)
  • Author(s): Nobuhiro Nakano, Chiharu Nishiyama, Hideo Yagita, Ko Okumura, and Hideoki Ogawa
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Notchシグナルによるマスト細胞のTh2サイトカイン産生増強メカニズムの解析 (2015)
  • Author(s): 中野信浩、西山千春、八木田秀雄、奥村康、小川秀興
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都・品川区）
  • Year and Date: 2015-05-26
• [Remarks] 順天堂大学大学院医学研究科アトピー疾患研究センターのホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/