Search for new molecules controlling the response of nucleic acid-sensing TLRs

• Project/Area Number: 25460585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: FUKUI Ryutaro 東京大学, 医科学研究所, 助教 (60554508)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 自然免疫 / 自己免疫疾患 / Toll-like receptor / 核酸認識 / I型インターフェロン / Unc93 homolog B1 / 新規分子探索 / 自然炎症 / ファンクショナルクローニング / sgRNAライブラリ / ゲノム編集 / 連鎖解析 / TLR7 / 新規分子 / 遺伝子改変マウス / 核酸認識系TLR応答調節 / 表現型調節因子

Outline of Final Research Achievements

We tried functional cloning to find new molecules controlling the response of nucleic acid-sensing Toll-like receptors (TLRs), like TLR7. As the other way, we analyzed the phenotype of Unc93 homolog B1 (Unc93B1) D34A mutant mice, which suffer from systemic inflammation caused by TLR7 hyperactivation
As results, we found that the phenotype of D34A mice was attenuated by lacking type I interferon receptor (IFNAR1). Type I IFN signaling maintained the expression of TLR7 in B cells, and the number of TLR7-expressing conventional dendritic cells, respectively.

Research Products

• [Journal Article] Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells (2016)
  • Author(s): Fukui R, Kanno A, Miyake K
  • Journal Title: J Immunol Volume: 196 Issue: 1 Pages: 416-427
  • DOI: 10.4049/jimmunol.1500071
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases (2015)
  • Author(s): Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y, Onji M, Fukui R, Shimozato T, Yamamoto K, Shibata T, Sano S, Sugahara-Tobinai A, Takai T, Ohto U, Shimizu T, Saitoh S, Miyake K.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 6119-6119
  • DOI: 10.1038/ncomms7119
  • Peer Reviewed / Open Access
• [Journal Article] DNase II-dependent DNA digestion is required for DNA sensing by TLR9 (2015)
  • Author(s): Chan MP, Onji M, Fukui R, Kawane K, Shibata T, Saitoh SI, Ohto U, Shimizu T, Barber GN, *Miyake K
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 5853-5853
  • DOI: 10.1038/ncomms6853
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Roles of the Cleaved N-Terminal TLR3 Fragment and Cell Surface TLR3 in Double-Strand RNA Sensing (2015)
  • Author(s): Murakami Y, Fukui R, Motoi Y, Kanno A, Shibata T, Tanimura N, Saitoh S, Miyake K
  • Journal Title: Journal of Immunology Volume: 193 Issue: 10 Pages: 5208-5217
  • DOI: 10.4049/jimmunol.1400386
  • Peer Reviewed
• [Journal Article] An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing (2013)
  • Author(s): Onji M, Kanno A, Saitoh S, Fukui R, Motoi Y, Shibata T, Matsumoto F, Lamichhane A, Sato S, Kiyono H, Yamamoto K, Miyake K
  • Journal Title: Nat. Commun. Volume: 4 Issue: 1 Pages: 1949-1949
  • DOI: 10.1038/ncomms2949
  • NAID: 120005359107
  • Peer Reviewed
• [Journal Article] Double-stranded RNA of small intestinal commensal but not pathogenic bacteria triggers TLR3-mediated IFN-β production by dendritic cells (2013)
  • Author(s): T. Kawashima, A. Kosaka, H. Yan, G. Zijin, R. Uchiyama, R. Fukui, D. Kaneko; Y. Kumagai; D.-J. You, J. Carreras, S. Uematsu, M. H. Jang, O. Takeuchi, T. Kaisho, S. Akira, K. Miyake, H. Tsutsui, T. Saito, I. Nishimura, N. M. Tsuji
  • Journal Title: Immunity Volume: 38 Issue: 6 Pages: 1187-1197
  • DOI: 10.1016/j.immuni.2013.02.024
  • Peer Reviewed
• [Presentation] I型インターフェロンはB細胞と樹状細胞のTLR7発現を維持し、TLR7の過剰応答による致死的な炎症に関与する. (2015)
  • Author(s): 福井竜太郎, 菅野敦夫, 三宅健介.
  • Organizer: 第80回日本インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 東京工業大学蔵前会館
  • Year and Date: 2015-07-17
• [Presentation] Expression patterns of TLR7 in DCs and B cells are controlled by Type-I IFN and influence TLR7 dependent inflammation (2014)
  • Author(s): Ryutaro Fukui, Atsuo Kanno and Kensuke Miyake
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館, 京都府
  • Year and Date: 2014-12-10
• [Presentation] shRNAライブラリーを用いたファンクショナルクローニングによるTLR7応答の制御因子の探索 (2014)
  • Author(s): 高橋紀子, 福井竜太郎, 三宅健介
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜, 神奈川県
  • Year and Date: 2014-11-25
• [Presentation] Collapse of TLR7/TLR9 balance leads genetical background dependent phenotypes (2013)
  • Author(s): Ryutaro Fukui and Kensuke Miyake
  • Organizer: 第１５回 国際免疫学会
  • Place of Presentation: イタリア・ミラノ
• [Presentation] Search for regulatory molecules of nucleic acid sensing Toll-like receptors dependent systemic inflammation (2013)
  • Author(s): Ryutaro Fukui and Kensuke Miyake
  • Organizer: 第４３回 日本免疫学会
  • Place of Presentation: 日本・幕張
• [Remarks] 感染遺伝学分野ホームページ・発表論文
  • URL: http://www.ims.u-tokyo.ac.jp/kanseniden/public/
• [Remarks] 東京大学医科学研究所 感染遺伝学分野webサイト
  • URL: http://www.ims.u-tokyo.ac.jp/kanseniden/index.html
• [Remarks] 国際科学技術財団 研究助成ブログ
  • URL: http://blog2014fukui.japanprize.jp