Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms4492
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Funding
- Funding Program for World-leading Innovative R&D on Science and Technology (FIRST Program) of the Japanese Society for the Promotion of Science (JSPS)
- JSPS
- Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare in Japan
- Senri Life Science Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Program for Promotion of Basic and Applied Research for Innovations in Bio-oriented Industry
- Ministry of Education, Culture, Sports, Science and Technology of Japan for the Leading-edge Research Infrastructure Program
- Ministry of Health and Welfare of Japan
- Yakult Bio-Science Foundation
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High-dose ionizing radiation induces severe DNA damage in the epithelial stem cells in small intestinal crypts and causes gastrointestinal syndrome (GIS). Although the tumour suppressor p53 is a primary factor inducing death of crypt cells with DNA damage, its essential role in maintaining genome stability means inhibiting p53 to prevent GIS is not a viable strategy. Here we show that the innate immune receptor Toll-like receptor 3 (TLR3) is critical for the pathogenesis of GIS. Tlr3(-/-) mice show substantial resistance to GIS owing to significantly reduced radiation-induced crypt cell death. Despite showing reduced crypt cell death, p53-dependent crypt cell death is not impaired in Tlr3(-/-) mice. p53-dependent crypt cell death causes leakage of cellular RNA, which induces extensive cell death via TLR3. An inhibitor of TLR3-RNA binding ameliorates GIS by reducing crypt cell death. Thus, we propose blocking TLR3 activation as a novel approach to treat GIS.
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