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

Nat Commun. 2014 Mar 18;5:3492. doi: 10.1038/ncomms4492.

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.

MeSH terms

  • Animals
  • Apoptosis
  • Female
  • Gastrointestinal Diseases / genetics
  • Gastrointestinal Diseases / metabolism*
  • Gastrointestinal Diseases / physiopathology
  • Gastrointestinal Diseases / prevention & control*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Radiation Injuries / genetics
  • Radiation Injuries / metabolism*
  • Radiation Injuries / physiopathology
  • Radiation Injuries / prevention & control*
  • Radiation, Ionizing
  • Toll-Like Receptor 3 / deficiency*
  • Toll-Like Receptor 3 / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Tumor Suppressor Protein p53