Analysis on molecular mechanisms of innate immune regulation via nucleic acids sensors and their roles in development of inflammatory diseases

• Project/Area Number: 17H04066
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nara Institute of Science and Technology
• Principal Investigator: Kawai Taro 奈良先端科学技術大学院大学, 先端科学技術研究科, 教授 (50456935)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 自然免疫 / ウイルス感染 / シグナル伝達 / 炎症 / サイトカイン / 炎症性疾患 / 樹状細胞

Outline of Final Research Achievements

Members of innate immune receptors such as Toll-like receptors, RIG-I-like receptors and cGAS mediate recognition of viral nucleic acids and play a critical role in host defense by promoting inflammation and shaping adaptive immune system. However, dysregulation of this recognition system causes autoimmune and inflammatory disorders. In this study, we identified several key molecules that regulate innate immune responses induced by these receptors, and analyzed their roles in host defense as well as immune diseases.

Academic Significance and Societal Importance of the Research Achievements

自然免疫受容体を介するウイルスや自己の核酸認識受容体を介する情報伝達経路の解析を中心とする本研究は、感染防御における自然免疫システムの役割を明らかにすることに繋がり学術的に重要である。同時に、自然免疫系を基盤とした研究は、ワクチン開発において必要である。一方、自然免疫系の破綻により自己免疫疾患が発症することがわかっているが、その詳細は明らかにされておらず、本研究を通して疾患治療に繋がることも期待される。中でも、抗がん剤により死滅したがん細胞から放出されたDNAが免疫賦活化活性を持つことを示した本研究成果は新たな腫瘍ワクチンの開発への足がかりになるものと期待される。

Research Products

• [Int'l Joint Research] マラヤ大学(マレーシア)
• [Journal Article] Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses (2020)
  • Author(s): Monwan Warunthorn、Kawasaki Takumi、Hasan Md Zobaer、Ori Daisuke、Kawai Taro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 4 Pages: 1077-1082
  • DOI: 10.1016/j.bbrc.2019.11.035
  • Peer Reviewed
• [Journal Article] Innate immune responses through Toll-like receptor 3 require human-antigen-R-mediated Atp6v0d2 mRNA stabilization (2019)
  • Author(s): Zainol Mohd Izwan Bin、Kawasaki Takumi、Monwan Warunthorn、Murase Motoya、Sueyoshi Takuya、Kawai Taro
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 20406-20406
  • DOI: 10.1038/s41598-019-56914-w
  • Peer Reviewed / Open Access
• [Journal Article] A Cytosolic Sensor, PmDDX41, Binds Double Stranded-DNA and Triggers the Activation of an Innate Antiviral Response in the Shrimp Penaeus monodon via the STING-Dependent Signaling Pathway. (2019)
  • Author(s): Soponpong S, Amparyup P, Kawai T, Tassanakajon A.
  • Journal Title: Front Immunol. Volume: 10 Pages: 2069-2069
  • DOI: 10.3389/fimmu.2019.02069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome organization and definition of the Penaeus monodon viral responsive protein 15 (PmVRP15) promoter. (2019)
  • Author(s): Jaree P, Kawai T, Lo CF, Tassanakajon A, Somboonwiwat K.
  • Journal Title: Fish Shellfish Immunol. Volume: 93 Pages: 997-1006
  • DOI: 10.1016/j.fsi.2019.08.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Penaeus monodon IKKs Participate in Regulation of Cytokine-Like System and Antiviral Responses of Innate Immune System. (2019)
  • Author(s): Nhnhkorn Z, Amparyup P, Kawai T, Tassanakajon A.
  • Journal Title: Front Immunol. Volume: 10 Pages: 1430-1430
  • DOI: 10.3389/fimmu.2019.01430
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking (2019)
  • Author(s): Putri DDP, Kawasaki T, Murase M, Sueyoshi T, Deguchi T, Ori D, Suetsugu S, Kawai T.
  • Journal Title: J Biol Chem Volume: - Issue: 21 Pages: 8412-8423
  • DOI: 10.1074/jbc.ra118.005731
  • Peer Reviewed / Open Access
• [Journal Article] Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System. (2019)
  • Author(s): Kawasaki T, Kawai T.
  • Journal Title: Int Rev Cell Mol Biol. Volume: 344 Pages: 1-30
  • DOI: 10.1016/bs.ircmb.2018.08.004
  • ISBN: 9780128159798
  • Peer Reviewed
• [Journal Article] Sensing Self and Non-Self DNA by Innate Immune Receptors and Their Signaling Pathways. (2018)
  • Author(s): Sok SPM, Ori D, Nagoor NH, Kawai T.
  • Journal Title: Crit Rev Immunol. Volume: 38 Issue: 4 Pages: 279-301
  • DOI: 10.1615/critrevimmunol.2018026540
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2. (2018)
  • Author(s): Sueyoshi T, Kawasaki T, Kitai Y, Ori D, Akira S, Kawai T.
  • Journal Title: J Immunol. Volume: 200 Issue: 11 Pages: 3814-3824
  • DOI: 10.4049/jimmunol.1701282
  • Peer Reviewed
• [Journal Article] Intravesicular Acidification Regulates Lipopolysaccharide Inflammation and Tolerance through TLR4 Trafficking. (2018)
  • Author(s): Murase M, Kawasaki T, Hakozaki R, Sueyoshi T, Putri DDP, Kitai Y, Sato S, Ikawa M, Kawai T.
  • Journal Title: J Immunol. Volume: -- Issue: 8 Pages: 2798-2808
  • DOI: 10.4049/jimmunol.1701390
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deletion of PIKfyve alters alveolar macrophage populations and exacerbates allergic inflammation in mice. (2017)
  • Author(s): Kawasaki T, Ito K, Miyata H, Akira S, Kawai T.
  • Journal Title: EMBO J. Volume: 36 Issue: 12 Pages: 1707-1718
  • DOI: 10.15252/embj.201695528
  • NAID: 120006309714
  • Peer Reviewed
• [Journal Article] Cytosolic nucleic acid sensors and innate immune regulation. (2017)
  • Author(s): Ori D, Murase M, Kawai T.
  • Journal Title: Int Rev Immunol. Volume: 36 Issue: 2 Pages: 74-88
  • DOI: 10.1080/08830185.2017.1298749
  • Peer Reviewed
• [Journal Article] Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. (2017)
  • Author(s): Kozaki T, Komano J, Kanbayashi D, Takahama M, Misawa T, Satoh T, Takeuchi O, Kawai T, Shimizu S, Matsuura Y, Akira S, Saitoh T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 10 Pages: 2681-2686
  • DOI: 10.1073/pnas.1621508114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DNA-Containing Exosomes Derived from Cancer Cells Treated with Topotecan Activate a STING-Dependent Pathway and Reinforce Antitumor Immunity (2017)
  • Author(s): Kitai Y, Kawasaki T, Sueyoshi T, Kobiyama K, Ishii KJ, Zou J, Akira S, Matsuda T, Kawai T.
  • Journal Title: J. Immunol. Volume: 198 Issue: 4 Pages: 1649-1659
  • DOI: 10.4049/jimmunol.1601694
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] DNA methylation of CpG dinucleotides in the IL-6 gene promoter regulates the level of IL-6 gene expression (2019)
  • Author(s): Benedict Shi Xiang Lian, Daisuke Ori, Takumi Kawasaki, Taro Kawai
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Molecular mechanisms of Imiquimod (IMQ)-induced cell death and its role in inflammation (2019)
  • Author(s): Haruna Okude, Daisuke Ori, Takumi Kawasaki, Masatoshi Momota, Ken J Ishii, Masahiro Yamamoto, Taro Kawai
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] The effects of immunomoduratory drug on NLRP3 inflammasome activation (2019)
  • Author(s): Guang Han Ong, Daisuke Ori, Takumi Kawasaki, Taro Kawai
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Inhibitory effects of 1-acetoxychavicol acetate (ACA), a ginger-derived compound, on monosodium urate (MSU) crystal-induced neutrophil recruitment in vivo (2019)
  • Author(s): Daisuke Ori, Sophia Ping Meow Sok, Nagoor Noor Hasima, Taro Kawai
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] 肺内でのCD8陽性T細胞の誘導における組織特異的マクロファージの役割 (2019)
  • Author(s): 河合 太郎、川崎 拓実
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Imiquimod(IMQ)による細胞死と炎症誘導機構の解析 (2019)
  • Author(s): 奥出遥奈、織大祐、川崎拓実、百田匡寿、石井健、山本雅裕、河合太郎
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] The role of innate immune signaling pathways in induction of anti-cancer immunity (2019)
  • Author(s): Kawai T
  • Organizer: THE 6th ICPAPS & The 3rd ASEAN PHARMNET 2019
  • Int'l Joint Research / Invited
• [Presentation] 自然免疫による病原体や内在性因子の認識と炎症制御のメカニズムについて (2019)
  • Author(s): 河合太郎
  • Organizer: 免疫サマースクール2019
  • Invited
• [Presentation] ウイルスや自己の核酸に対する自然免疫応答について (2018)
  • Author(s): 河合太郎
  • Organizer: 日本ウイルス学会北海道支部第52回夏季シンポジウム（上砂川岳温泉パンケの湯・北海道空知郡上砂川町）
  • Invited
• [Presentation] 自然免疫受容体やそれらのシグナル伝達分子を標的とした疾患制御の可能性について (2018)
  • Author(s): 河合太郎
  • Organizer: 第1回 Trans Chromosomics (TC) シンポジウム（鳥取大学医学部・鳥取県米子市）
  • Invited
• [Presentation] Human antigen R regulates innate immune response via mRNA stability (2018)
  • Author(s): Mohd Izwan Zainol, Takumi Kawasaki, Taro Kawai
  • Organizer: 第47回日本免疫学会学術総会（福岡国際会議場・福岡）
• [Presentation] Regulatory role of MTMR3/4 in innate immune signaling (2018)
  • Author(s): Takumi Kawasaki, Dyaningtyas Dewi Pamungkas Putri, Taro Kawai
  • Organizer: 第47回日本免疫学会学術総会（福岡国際会議場・福岡）
• [Presentation] Inhibition of NLRP3 in ammasome-mediated IL-1 release by 1'-acetoxychavicol acetate (ACA), a ginger-derived compound (2018)
  • Author(s): Sophia Ping Meow Sok, Daisuke Ori, Noor Hasima Nagoor, Taro Kawai
  • Organizer: 第47回日本免疫学会学術総会（福岡国際会議場・福岡）
• [Presentation] Molecular mechanism of IL-33 production during allergic inflammation (2018)
  • Author(s): Mizuka nagayama, Takumi Kawasaki, Taro Kawai
  • Organizer: 第47回日本免疫学会学術総会（福岡国際会議場・福岡）
• [Presentation] Identification of Nucleoporin (Nup) genes that mediate antiviral innate immune responses. (2018)
  • Author(s): Monwan, W., Kawasaki, T. Kawai T.
  • Organizer: The 6th International Conference on Biochemistry and Molecular Biology "Networking in molecular biosciences towards creativity and innovation"（Rayong Resort・Rayong, Thailand）
• [Presentation] Elucidation of cell death pathway induced by imiquimod (R837) (2018)
  • Author(s): Haruna Okude, Daisuke Ori, Takumi Kawasaki, Motoya Murase, Ken J Ishii, Taro Kawai
  • Organizer: EMBO Workshop "The inflammasomes" （Max-Planck-Institute of Biochemistry・Martinsried, Germany）
• [Presentation] Tropical ginger compound, 1'-acetoxychavicol acetate (ACA), inhibits NLRP3 inflammasome activation (2018)
  • Author(s): Sophia Ping Meow Sok, Daisuke Ori, Noor Hasima Nagoor, Taro Kawai
  • Organizer: EMBO Workshop "The inflammasomes" （Max-Planck-Institute of Biochemistry・Martinsried, Germany）
• [Presentation] TMEM41a negatively regulates antiviral immune responses (2018)
  • Author(s): Miyu Nakagawa, Taro Kawai
  • Organizer: 第41回日本分子生物学会年会（パシフィコ横浜・横浜市）
• [Presentation] Molecular mechanism of IL-33 production during allergic inflammation (2018)
  • Author(s): Mizuka Nagayama, Takumi Kawasaki, Taro Kawai
  • Organizer: 第41回日本分子生物学会年会（パシフィコ横浜・横浜市）
• [Presentation] Negative regulation of RIG-I mediated antiviral innate immune responses by TMEM41a (2018)
  • Author(s): Miyu Nakagawa, Taro Kawai
  • Organizer: The 7th Global Network Forum Infection and Immunity（千葉大学医学部付属病院 ・千葉市）
• [Presentation] Molecular mechanism of IL-33 production during allergic inflammation (2018)
  • Author(s): Mizuka Nagayama, Takumi Kawasaki, Taro Kawai
  • Organizer: The 7th Global Network Forum Infection and Immunity （千葉大学医学部付属病院 ・千葉市）
• [Presentation] Induction of cell death by imiquimod (R837) and its role in immune responses (2017)
  • Author(s): Okude H, Ori D, Kawasaki T, Mruase M, Ishii KJ, Kawai T
  • Organizer: 第46回日本免疫学会学術集会（仙台国際センター・宮城県仙台市）
• [Presentation] RNA-binding protein Hu antigen R (HuR) plays an important role in antiviral innate immune responses via mRNA stabilization (2017)
  • Author(s): Sueyoshi T, Kawasaki T, Kawai T
  • Organizer: 第46回日本免疫学会学術集会（仙台国際センター・宮城県仙台市）
• [Presentation] Obesity regulation by PIKfyve, a lipid kinase, in macrophage (2017)
  • Author(s): Kawasaki T, Kawai T
  • Organizer: 第46回日本免疫学会学術集会（仙台国際センター・宮城県仙台市）
• [Presentation] Intravesicular acidification regulates lipopolysaccharide inflammation and tolerance through Toll-like receptor 4 trafficking (2017)
  • Author(s): Murase M, Kawaaki T, Hakozaki R, Kawai T
  • Organizer: 第46回日本免疫学会学術集会（仙台国際センター・宮城県仙台市）
• [Presentation] Characterization of Nucleoporin (Nup) genes that mediate antimicrobial innate immune responses (2017)
  • Author(s): Monwan W, Kawasaki T, Kawai T
  • Organizer: 第46回日本免疫学会学術集会（仙台国際センター・宮城県仙台市）
• [Presentation] RNA 結合タンパク質 Hu antigen R(HuR) のウイルスに対する自然免疫における役割の解析 (2017)
  • Author(s): 末吉拓也、川崎拓実、河合太郎
  • Organizer: 生命科学系学会合同年次大会（神戸ポートアイランド・兵庫県神戸市）
• [Presentation] Imiquimod(R837) による TLR7非依存的な細胞死の誘導 (2017)
  • Author(s): 奥出遥奈、織大佑、川崎拓実、村瀬本弥、河合太郎
  • Organizer: 生命科学系学会合同年次大会（神戸ポートアイランド・兵庫県神戸市）
• [Presentation] V 型 ATPase のサブユニット ATP6V0D2による ARF6を介した Toll-like receptor 4(TLR4)の細胞内輸送と LPS の 日目 認識で誘導される炎症応答・LPS トレランスの制御機構の解明 (2017)
  • Author(s): 村瀬本弥、川崎拓実、箱崎理花、河合太郎
  • Organizer: 生命科学系学会合同年次大会（神戸ポートアイランド・兵庫県神戸市）
• [Presentation] IL-33産生を制御する分子機構の解明 (2017)
  • Author(s): 長山瑞佳、川崎拓実、河合太郎
  • Organizer: 生命科学系学会合同年次大会（神戸ポートアイランド・兵庫県神戸市）
• [Presentation] The role of innate immune signaling pathways in anti-cancer immunity (2017)
  • Author(s): Kawai T
  • Organizer: 2nd International Conference on Molecular Biology and Biotechnology（クアラルンプール・マレーシア）
  • Int'l Joint Research / Invited
• [Book] 免疫・炎症病態×治療Update (2019)
  • Author(s): 加納規資, 織大祐, 河合太郎
  • Total Pages: 9
  • Publisher: 南山堂
  • ISBN: 9784525167813
• [Book] 血液内科 (2017)
  • Author(s): 奥出遥奈、中川実優、川崎拓実、河合太郎
  • Total Pages: 7
  • Publisher: 科学評論社
• [Book] 炎症と免疫 (2017)
  • Author(s): 鍛代悠一、河合太郎
  • Total Pages: 6
  • Publisher: 先端医学社