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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Takemura N,Kawasaki T,Kunisawa J,Sato S,Lamichhane A,Kobiyama K,Aoshi T,Ito J,Mizuguchi K,Karuppuchamy T,Matsunaga K,Miyatake S,Mori N,Tsujimura T,Satoh T,Kumagai Y,Kawai T,Standley DM,Ishii KJ,Kiyono H,Akira S,

doi

10.1038/ncomms4492

subject

Has Abstract

pub_date

2014-03-18 00:00:00

pages

3492

issn

2041-1723

pii

ncomms4492

journal_volume

5

pub_type

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