The Institute of Medical Science, The University Of Tokyo

  1. Home
  2. Scientific Papers

Scientific Papers/Award

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

Nature Communications 5, 3492 doi:10.1038/ncomms4492
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 & Satoshi Uematsu
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

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.