Elucidation of the molecular mechanism involved in TLR7/8 response to ssRNA

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08827
• 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: Shibata Takuma 東京大学, 医科学研究所, 助教 (30554505)
• Research Collaborator: Sato Ryota ; Liu Kaiwen
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: Toll Like Receptor / TLR7 / TLR8 / ssRNA

Outline of Final Research Achievements

TLR7 in the endolysosome is a sensor for single-stranded RNA (ssRNA) fromviruses and it induces antiviral immune response. In addition, this receptor also responds to synthetic small molecules such as R848 and Imiquimod. However,it remains unclear how and why TLR7 can sense these two distinct ligands. We have found that TLR7 recognized guanosine (G),in the presence of uridine-containing oligoribonucleotide (U-ORN). With U-ORN, G/dG synergistically activated TLR7 and induced cytokine production in macrophages and pDCs. These results strongly suggest that TLR7 recognizes degradation products of ssRNA, G and U-ORN, but not ssRNA itself. Additionally, we have found that SLC29A3 deficient mice, which lose nucleoside transporter in endolysosomes, show autoinflammatory disease in TLR7-dependent manner. Our findings reveal that TLR7 works as a guanosine sensor and the appropriate control of nucleoside metabolism is indispensable for preventing excessive TLR7 response in vivo.

Free Research Field

免疫

Academic Significance and Societal Importance of the Research Achievements

TLR7やTLR8は抗ウイルス応答の誘導に加えて自己免疫疾患や自己炎症性疾患の原因となっていることが以前から示唆されている。しかし、生体内においてTLR7/8の過剰応答が誘導される原因は良く分かっていなかった。本研究では、TLR7/8によるssRNA認識に核酸代謝関連遺伝子が関与することを証明すると共に、それら遺伝子のマウスにおける機能欠損が生体内でのTLR7/8過剰活性化を引き起こすことも示された。以上の事実は、核酸代謝関連遺伝子の機能異常がTLR7/8応答を介した病態の発症につながることを示唆しており、今後ヒトにおいてTLR7/8が関与した疾患の発見につながると期待される。