Elucidation of mechanisms underlying IL-23 production from dendritic cells in refractory asthma

• Project/Area Number: 25461492
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Chiba University
• Principal Investigator: Tamachi Tomohiro 千葉大学, 医学(系)研究科(研究院), 助教 (20456015)
• Co-Investigator(Kenkyū-buntansha): HIROSE Koichi 千葉大学, 大学院医学研究院, 准教授 (90400887) ; TAKATORI Hiroaki 千葉大学, 医学部附属病院, 助教 (30568225)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 難治性喘息 / IL-23 / 樹状細胞 / 気道上皮細胞

Outline of Final Research Achievements

To elucidate the underlying mechanisms of refractory asthma, our objective was to identify the factor that induces IL-23 production from dendritic cells. We also aimed to clarify the roles of Dectin-2, a C-type lectin receptor for fungal α-mannan, expressed on dendritic cells and the roles of IκBNS expressed in hematopoietic cells in HDM-induced allergic airway inflammation.
We found Dectin-2 expressed on CD11b+ DCs induced IL-23 expression and promoted HDM-induced airway inflammation. We also found CD11b+ DCs isolated from Dectin-2-deficent mice expressed lower levels of proinflammatory cytokines and co-stimulatory molecules which could lead to Th2 and Th17 cell differentiation than those from wild-type mice. In addition, we found HDM-induced airway inflammation was exacerbated in mice lacking IκBNS in hematopoietic cells. We are currently searching for epithelial cell-derived factors that induce IL-23 production from dendritic cells in asthma by a novel co-culture approach.

Research Products

• [Journal Article] Helios enhances regulatory T cell function in cooperation with Foxp3 (2015)
  • Author(s): Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K, Suto A, Suzuki K, Kagami S, Hirose K, Kubo M, Hori S, Nakajima H
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 6 Pages: 1491-502
  • DOI: 10.1002/art.39091
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MMP12 is produced by M2 monocytes-macrophages and plays important roles in the development of contact hypersensitivity (2015)
  • Author(s): Nakagomi D, Suzuki K, Meguro K, Hosokawa J, Tamachi T, Takatori H, Suto A, Matsue H, Ohara O, Nakayama T, Shimada S, Nakajima H
  • Journal Title: J Allergy Clin Immunol Volume: 135 Issue: 5 Pages: 1397-400
  • DOI: 10.1016/j.jaci.2014.10.055
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sox5 and c-Maf cooperatively induce Th17 cell differentiation via ROR gamma t induction as downstream targets of Stat3 (2014)
  • Author(s): Tanaka S, Suto A, Iwamoto T, Kashiwakuma D, Kagami S, Suzuki K, Takatori H, Tamachi T, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashita M, Nakayama T, Nakajima H
  • Journal Title: J Exp Med Volume: 211 Issue: 9 Pages: 1857-1874
  • DOI: 10.1084/jem.20130791
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dectin-2 promotes house dust mite-induced Th2 and Th17 cell differentiation and allergic airway inflammation in mice. (2014)
  • Author(s): Norimoto A, Hirose K, Tamachi T, Nakajima H et al.
  • Journal Title: Am J Respir Cell Mol Biol Volume: Mar 3. [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity. (2014)
  • Author(s): Iwata A, Kawashima S, Kobayashi M, Okubo A, Kawashima H, Suto A, Hirose K, Nakayama T, Nakajima H
  • Journal Title: Int Immunol Volume: 26 Issue: 2 Pages: 103-114
  • DOI: 10.1093/intimm/dxt047
  • Peer Reviewed
• [Journal Article] IL-25 induces pulmonary arterial remodeling by NKT cell-dependent mechanisms (2013)
  • Author(s): Kawashima S, Hirose K, Takahashi K, Tamachi T, Ikeda K, Tokoyoda K, Nakayama T, Nakajima H
  • Journal Title: Int Arch Allergy Immunol Volume: 161, Suppl Issue: Suppl. 2 Pages: 118-124
  • DOI: 10.1159/000350379
  • Peer Reviewed
• [Presentation] 気道上皮細胞に発現するIκBNSのアレルギー性気道炎症における役割 (2016)
  • Author(s): 玉地智宏、横田雅也、横山祐亮、前沢裕子、須藤明、鈴木浩太郎、廣瀬晃一、中島裕史
  • Organizer: 日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2016-06-19
• [Presentation] Dectin-1 expressed on CD11b+ dendritic cells promotes house dust mite-induced allergic airway inflammation in mice. (2015)
  • Author(s): Ito T, Hirose K, Saijo S, Iwakura Y, Nakajima H
  • Organizer: 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: 2015-11-20
• [Presentation] Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3. (2014)
  • Author(s): Tanaka S, Suto A, Iwamoto T, Takatori H, Tamachi T, Suzuki K, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashita M, Nakayama T, Nakajima H.
  • Organizer: 日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Year and Date: 2014-12-12
• [Presentation] チリダニ誘発性アレルギー性気道炎症発症における真菌認識機構Dectin-2の役割 (2013)
  • Author(s): 大久保綾子、廣瀬晃一、西城忍、岩倉洋一郎、中島裕史
  • Organizer: 日本アレルギー学会秋期学術大会
  • Place of Presentation: 東京、ホテルニューオータニ
• [Presentation] スエヒロタケ特異的IgE抗体測定ELISA法による喘息患者における感作率の検討 (2013)
  • Author(s): 廣瀬晃一、豊留孝仁、亀井克彦、岩本逸夫、中島裕史
  • Organizer: 日本アレルギー学会春期臨床大会
  • Place of Presentation: 横浜、パシフィコ横浜
• [Presentation] 腸管免疫と脊椎関節炎
  • Author(s): 玉地智宏
  • Organizer: 日本脊椎関節炎学会学術集会
  • Place of Presentation: 東京、京王プラザホテル
  • Invited