Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome.
Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome.
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DOI：
10.1038/ncomms4492
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发表时间：
2014-03-18
影响因子：
16.6
通讯作者：
Uematsu, Satoshi
中科院分区：
文献类型：
--
作者：
Takemura, Naoki;Kawasaki, Takumi;Kunisawa, Jun;Sato, Shintaro;Lamichhane, Aayam;Kobiyama, Kouji;Aoshi, Taiki;Ito, Junichi;Mizuguchi, Kenji;Karuppuchamy, Thangaraj;Matsunaga, Kouta;Miyatake, Shoichiro;Mori, Nobuko;Tsujimura, Tohru;Satoh, Takashi;Kumagai, Yutaro;Kawai, Taro;Standley, Daron M.;Ishii, Ken J.;Kiyono, Hiroshi;Akira, Shizuo;Uematsu, Satoshi
大剂量电离辐射可引起小肠隐窝上皮干细胞DNA严重损伤，引起胃肠道综合征。尽管抑癌基因P53是导致DNA损伤的隐窝细胞死亡的主要因素，但其在维持基因组稳定方面的重要作用意味着通过抑制P53来预防GIS并不是一个可行的策略。在此，我们认为先天免疫受体Toll样受体3(TLR3)在GIS的发病机制中起着关键作用。TLR3型−/−小鼠由于显著减少了辐射诱导的隐窝细胞死亡而显示出对地理信息系统的实质性抵抗力。尽管TLR3−/−小鼠的隐窝细胞死亡减少，但依赖于P53的隐窝细胞死亡并未受到损害。P53依赖的隐窝细胞死亡导致细胞RNA的泄漏，从而通过TLR3诱导广泛的细胞死亡。一种TLR3-RNA结合的抑制剂通过减少隐窝细胞的死亡来改善GIS。因此，我们建议阻断TLR3的激活作为治疗GIS的一种新方法。电离辐射会损害小肠隐窝细胞，包括上皮干细胞及其后代。在这里，作者表明，辐射诱导的隐窝细胞死亡是通过从凋亡的上皮细胞释放细胞RNA放大的，然后触发邻近细胞上的促凋亡TLR3信号。
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. Ionizing radiation damages small intestinal crypt cells, including epithelial stem cells and their progeny. Here the authors show that radiation-induced crypt cell death is amplified by the release of cellular RNA from apoptotic epithelial cells, which then triggers pro-apoptotic TLR3 signalling on neighbouring cells.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.4
作者：
Kaiser, WJ;Offermann, MK
通讯作者：
Offermann, MK
DOI：
10.1073/pnas.0504830102
发表时间：
2005-09-13
影响因子：
11.1
作者：
Crawford, PA;Gordon, JI
通讯作者：
Gordon, JI
影响因子：
1.1
作者：
Gosselin, Tracy K;Mautner, Beatrice
通讯作者：
Mautner, Beatrice
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
通讯作者：
Yuan, Junying