:The roles of Semaphorin3G in the pathogenesis of rheumatoid arthritis

• Project/Area Number: 19K17902
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Chiba University
• Principal Investigator: Tanaka Shigeru 千葉大学, 医学部附属病院, 助教 (30822051)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 関節リウマチ / セマフォリン / マクロファージ

Outline of Research at the Start

関節リウマチは原因不明の慢性破壊性関節炎である。近年治療法の進歩により症状の改善が得られる患者が増えているが、依然として寛解（痛みや腫れがない状態）に至らない例も数多い。本研究では網羅的な遺伝子発現解析結果から、新規の治療標的となりうるセマフォリン３Gに着目し、マウス関節炎モデルおよび関節リウマチ患者の関節組織を用いた検討を行う。本研究により関節リウマチ治療の進歩が期待される。

Outline of Final Research Achievements

This project aimed to find novel therapeutic targets for rheumatoid arthritis patients. We previously performed unbiased gene-expression analyses of helper T cells from rheumatoid arthritis patients and found Semaphorin3G is a molecule which might be related to the pathogenesis of rheumatoid arthritis.
Semaphorin3G was expressed in the synovium of rheumatoid arthritis patients and arthritic mouse joint. The receptor for Semaphorin3G was expressed on macrophages. Mice lacking Semaphorin3G were resistant to murine arthritis model. Together, it is plausible that Semaphorin3G is a novel therapeutic target of rheumatoid arthritis patients.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチは慢性破壊性の関節炎であり、日本では約70万人の患者が存在する。疾患のコントロールが不良の場合、関節が破壊されることでその機能が制限され、生活の質や労働生産性が著しく低下する重大な疾患である。
現在の関節リウマチ治療は炎症を抑え、「寛解（＝症状がほとんどない状態）」を目標とするが「根治（＝薬を必要としない状態）」には至らない。今までの治療法とは異なる戦略を構築するを目標とする本研究により、次世代の「根治」を目指す次世代のリウマチ治療を提案する基盤となることが期待される。

Research Products

• [Journal Article] T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice (2020)
  • Author(s): Makita S, Takatori H, Matsuki A, Kawashima, Iwata A, Tanaka S, Nakagomi D, Oya Y, Matsumura R, Tamachi T, Suto A, Suzuki K, Hirose K, Nakajima H
  • Journal Title: J Invest Dermatol. Volume: Online ahead of print Issue: 5 Pages: 1274-1285
  • DOI: 10.1016/j.jid.2020.08.029
  • Peer Reviewed / Open Access
• [Journal Article] RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells. (2020)
  • Author(s): Makita S, Takatori H, Iwata A, Tanaka S, Furuta S, Ikeda K, Suto A, Suzuki K, Ramos SBV, Nakajima H.
  • Journal Title: Front Immunol. Volume: 11 Pages: 1291-1300
  • DOI: 10.3389/fimmu.2020.01291
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells (2020)
  • Author(s): Suehiro Ken-Ichi、Suto Akira、Suga Kensuke、Furuya Hiroki、Iwata Arifumi、Iwamoto Taro、Tanaka Shigeru、Kageyama Takahiro、Suzuki Kotaro、Hirose Koichi、Lefebvre V?ronique、Nakajima Hiroshi
  • Journal Title: Cellular & Molecular Immunology Volume: 0 Issue: 7 Pages: 0-0
  • DOI: 10.1038/s41423-020-0384-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Imbalance of Ly-6Chi and Ly-6Clo Monocytes/Macrophages Worsens Hyperoxia-Induced Lung Injury and Is Rescued by IFN-γ (2019)
  • Author(s): Eldredge Laurie C.、Creasy Rane S.、Tanaka Shigeru、Lai Jen-Feng、Ziegler Steven F.
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 9 Pages: 2772-2781
  • DOI: 10.4049/jimmunol.1801374
  • Peer Reviewed