Studying innate immune responses to nucleoside stress

• Project/Area Number: 19K22635
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAKE Kensuke 東京大学, 医科学研究所, 教授 (60229812)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 自然免疫 / Toll様受容体

Outline of Research at the Start

核酸はタンパク質を表す遺伝コードとして機能するばかりでなく、免疫コードとしても機能する。例えば、病原体コードとしてウィルス、細菌などの侵入を知らせる。また死細胞から放出され、組織傷害を示す。最近、構造生物学的な解析から、1重鎖RNAのセンサーと考えられてきたToll-like receptor 7 (TLR7)、TLR8がグアノシン(Guo)やウリジン(Uri)にも結合することが明らかになった。この結果を受けたさらなる展開として、ストレス応答におけるヌクレオシドの役割を解明することを本研究において解析し、どのような応答がヌクレオシドによって誘導され、どのような疾患と関与するのか、検討する。

Outline of Final Research Achievements

Toll-like receptor 7 (TLR7) and TLR8, innate immune sensors for single-stranded RNAs (ssRNAs), are expressed in macrophages and dendritic cells. The structures of TLR7 and TLR8 showed that they directly bind to nucleosides and short oligoribnucleotides, which are generated by RNA degradation in the endosomal compartment. TLR7/8 responses to nucleosides might activate the responses that are distinct from those induced by TLR7/8 responses to ssRNAs. We here studied in vivo macrophage responses to nucleosides, and found that macrophages accumulate when they are exposed to nucleosides and that TLR7 is expressed in accumulated macrophages. We will also study the relationship between TLR7 and V600E-BRAF, the somatic mutation driving human histiocytosis. We obtained mice expressing V600E in macrophages and studied expression of TLR7 in macrophage accumulation.

Academic Significance and Societal Importance of the Research Achievements

TLR7やTLR8は病原体センサーとして感染防御反応の誘導に関与していると考えられている。また、TLR7/8の活性化は様々な炎症性疾患の病態に関与すると考えられている。本研究では、TLR7、TLR8がヌクレオシドに結合するという知見を踏まえて、TLR7、TLR8のヌクレオシド他に対する応答を調べ、マクロファージの蓄積を誘導する可能性が示された。この知見は、TLR7、TLR8が関与する疾患の病態理解に資すると期待される。

Research Products

• [Journal Article] The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages (2020)
  • Author(s): Sato R, Reuter T, Hiranuma R, Shibata T, Fukui R, Motoi Y, Murakami Y, Tsukamoto H, Yamazaki S, Liu K, Saitoh SI, Latz E, Miyake K.
  • Journal Title: Int Immunol Volume: 32 Issue: 12 Pages: 785-798
  • DOI: 10.1093/intimm/dxaa055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase A2 from bee venom increases poly(I:C)-induced activation in human keratinocytes (2020)
  • Author(s): Nakashima Akina、Tomono Susumu、Yamazaki Tatsuya、Inui Masanori、Morita Naoko、Ichimonji Isao、Takagi Hidekazu、Nagaoka Fumiaki、Matsumoto Misako、Ito Yasuhiko、Yanagishita Takeshi、Miyake Kensuke、Watanabe Daisuke、Akashi-Takamura Sachiko
  • Journal Title: International Immunology Volume: - Issue: 6 Pages: 371-383
  • DOI: 10.1093/intimm/dxaa005
  • Peer Reviewed
• [Journal Article] Cytidine deaminase enables Toll-like receptor 8 activation by cytidine or its analogs. (2019)
  • Author(s): Furusho K, Shibata T, Sato R, Fukui R, Motoi Y, Zhang Y, Saitoh SI, Ichinohe T, Moriyama M, Nakamura S, Miyake, K.
  • Journal Title: International immunology. Volume: 31 Issue: 3 Pages: 167-173
  • DOI: 10.1093/intimm/dxy075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endolysosomal compartments as platforms for orchestrating innate immune and metabolic sensors (2019)
  • Author(s): Miyake Kensuke、Saitoh Shin‐ichiroh、Sato Ryota、Shibata Takuma、Fukui Ryutaro、Murakami Yusuke
  • Journal Title: Journal of Leukocyte Biology Volume: 106 Issue: 4 Pages: 853-862
  • DOI: 10.1002/jlb.mr0119-020r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 核酸に対する自然免疫応答と炎症性疾患 (2021)
  • Author(s): 三宅健介
  • Organizer: 医薬品研究開発にかかる発表会・セミナー
  • Invited
• [Presentation] Mechanisms controlling innate immune responses to nucleic acids (2020)
  • Author(s): Kensuke Miyake
  • Organizer: United States-Japan Coopertive Medical Science Program, The 22nd international conference on emerging infectious diseases in the pacific rim.
  • Int'l Joint Research / Invited
• [Presentation] 炎症による単球・マクロファージ増殖の分子基盤 (2020)
  • Author(s): 三宅健介
  • Organizer: 第41回日本炎症・再生医学会
  • Invited
• [Presentation] Mechanisms Controlling Innate Immune Responses to Nucleic Acids (2019)
  • Author(s): Kensuke Miyake
  • Organizer: The 3rd annual Chiba-UCSD symposium
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms Controlling Innate Immune Responses to Nucleic Acids (2019)
  • Author(s): Kensuke Miyake
  • Organizer: 5th workshop in biosciences, International Alliance of Research Internship (IARI) 2019
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms Controlling Innate Immune Responses to Nucleic Acids (2019)
  • Author(s): Kensuke Miyake
  • Organizer: The 26th international symposium on molecular cell biology of macrophages (MMCB2019)
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms Controlling Innate Immune Responses to Nucleic Acids (2019)
  • Author(s): Kensuke Miyake
  • Organizer: 52nd annual meeting of the society for leukocyte biology
  • Int'l Joint Research / Invited
• [Presentation] 核酸特異的Toll様受容体と自己免疫疾患 (2019)
  • Author(s): 三宅 健介
  • Organizer: 第47回日本臨床免疫学会
  • Invited