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Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome
Naoki Takemura1, Takumi Kawasaki2, Jun Kunisawa3
1Division 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.
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.
Insights
High-dose radiation causes gastrointestinal syndrome (GIS) by damaging intestinal stem cells. Blocking Toll-like receptor 3 (TLR3) activation prevents this damage, offering a new therapeutic strategy for GIS.
Area of Science:
- Radiation biology
- Immunology
- Gastroenterology
Background:
- High-dose ionizing radiation causes severe DNA damage in small intestinal crypt epithelial stem cells, leading to gastrointestinal syndrome (GIS).
- The tumor suppressor p53 is crucial for crypt cell death following DNA damage but inhibiting it to prevent GIS is not feasible due to its role in genome stability.
Purpose of the Study:
- To investigate the role of the innate immune receptor Toll-like receptor 3 (TLR3) in the pathogenesis of GIS.
- To explore the potential of targeting TLR3 as a therapeutic strategy for GIS.
Main Methods:
- Utilized Tlr3(-/-) mice to assess resistance to GIS after high-dose ionizing radiation.
- Examined p53-dependent crypt cell death and RNA leakage in irradiated Tlr3(-/-) mice.
- Tested the efficacy of a TLR3-RNA binding inhibitor in ameliorating GIS.
Main Results:
- Tlr3(-/-) mice exhibited significant resistance to GIS, characterized by reduced radiation-induced crypt cell death.
- p53-dependent crypt cell death was not impaired in Tlr3(-/-) mice, but leakage of cellular RNA induced by this process triggered TLR3-mediated cell death.
- Inhibition of TLR3-RNA binding effectively reduced crypt cell death and ameliorated GIS.
Conclusions:
- Toll-like receptor 3 (TLR3) plays a critical role in the development of gastrointestinal syndrome (GIS).
- Blocking TLR3 activation, particularly its interaction with leaked cellular RNA, presents a promising novel therapeutic approach for treating GIS.
