Studying innate immune responses to nucleoside stress

2020 Fiscal Year Final Research Report

• 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
• Keywords: 自然免疫

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.

Free Research Field

免疫学

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。