title: Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome.
abstract: 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.
authors.affiliation: Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takemura
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [3] Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawasaki
authors.affiliation: 1] Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.affiliation: 1] Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Aayam
authors.initials: A
authors.lastname: Lamichhane
authors.affiliation: 1] Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan [2] Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.affiliation: 1] Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan [2] Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Laboratory of Bioinformatics, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ito
authors.affiliation: Laboratory of Bioinformatics, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Thangaraj
authors.initials: T
authors.lastname: Karuppuchamy
authors.affiliation: Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Kouta
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Self Defense Gene Regulation, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-2 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8570, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Mori
authors.affiliation: Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.affiliation: 1] Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan [2] Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: 1] Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011832:Radiation Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D011839:Radiation, Ionizing; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D016159:Tumor Suppressor Protein p53