Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome

Naoki Takemura, Takumi Kawasaki, Jun Kunisawa, Shintaro Sato, Aayam Lamichhane, Kouji Kobiyama, Taiki Aoshi, Junichi Ito, Kenji Mizuguchi, Thangaraj Karuppuchamy, Kouta Matsunaga, Shoichiro Miyatake, Nobuko Mori, Tohru Tsujimura, Takashi Satoh, Yutaro Kumagai, Taro Kawai, Daron M. Standley, Ken J. Ishii, Hiroshi Kiyono, Shizuo Akira () and Satoshi Uematsu ()
Additional contact information
Naoki Takemura: International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo
Takumi Kawasaki: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University
Jun Kunisawa: Institute of Medical Science, The University of Tokyo
Shintaro Sato: Institute of Medical Science, The University of Tokyo
Aayam Lamichhane: Institute of Medical Science, The University of Tokyo
Kouji Kobiyama: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation
Taiki Aoshi: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation
Junichi Ito: Laboratory of Bioinformatics, National Institute of Biomedical Innovation
Kenji Mizuguchi: Laboratory of Bioinformatics, National Institute of Biomedical Innovation
Thangaraj Karuppuchamy: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University
Kouta Matsunaga: International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo
Shoichiro Miyatake: Laboratory of Self Defense Gene Regulation, Tokyo Metropolitan Institute of Medical Science
Nobuko Mori: Graduate School of Science, Osaka Prefecture University
Tohru Tsujimura: Hyogo College of Medicine
Takashi Satoh: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University
Yutaro Kumagai: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University
Taro Kawai: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST)
Daron M. Standley: Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University
Ken J. Ishii: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation
Hiroshi Kiyono: Institute of Medical Science, The University of Tokyo
Shizuo Akira: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University
Satoshi Uematsu: International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4492

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