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Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation

文献类型：期刊论文

作者Lian, Qiaoshi1,2,5; Xu, Jun3,5; Yan, Shanshan1,2,6; Huang, Min3; Ding, Honghua7; Sun, Xiaoyu4; Bi, Aiwei3; Ding, Jian3; Sun, Bing1,2,4; Geng, Meiyu3
刊名CELL RESEARCH
出版日期2017-06
卷号27期号:6页码:784-800
ISSN号1001-0602
关键词dsDNA AIM2 exosome inflammasome chemotherapy intestinal toxicity
DOI10.1038/cr.2017.54
文献子类Article
英文摘要Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, "self-DNA" released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome. This leads to mature IL-1 beta and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse inflammatory response.
WOS关键词METASTATIC COLORECTAL-CANCER ; ANTICANCER IMMUNE-RESPONSES ; CELL-DEATH ; IMMUNOGENIC TUMORS ; BOWEL-DISEASE ; SELF-DNA ; MUCOSITIS ; MICE ; IRINOTECAN ; MICROVESICLES
资助项目"Personalized Medicines - Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020102] ; Ministry of Science and Technology of China[2013CB530504] ; Ministry of Science and Technology of China[2016YFA0502202] ; Ministry of Science and Technology of China[2016YFA0502204] ; Chinese Academy of Sciences[XDB19000000] ; National Natural Science Foundation of China[81361120409] ; National Science and Technology Major Project[2015ZX09101009]
WOS研究方向Cell Biology
语种英语
CSCD记录号CSCD:6016603
出版者INST BIOCHEMISTRY & CELL BIOLOGY
WOS记录号WOS:000402545200009
源URL[http://119.78.100.183/handle/2S10ELR8/272644]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Huang, Min; Ding, Jian; Sun, Bing; Geng, Meiyu
作者单位1.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, 320 Yueyang Rd, Shanghai 200031, Peoples R China;
2.Univ Chinese Acad Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, 320 Yueyang Rd, Shanghai 200031, Peoples R China;
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
6.Univ Sci & Technol China, Sch Life Sci, Hefei 230022, Peoples R China;
7.Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Oncol, Shanghai 200080, Peoples R China
推荐引用方式
GB/T 7714		 Lian, Qiaoshi,Xu, Jun,Yan, Shanshan,et al. Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation[J]. CELL RESEARCH,2017,27(6):784-800.
APA Lian, Qiaoshi.,Xu, Jun.,Yan, Shanshan.,Huang, Min.,Ding, Honghua.,...&Geng, Meiyu.(2017).Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation.CELL RESEARCH,27(6),784-800.
MLA Lian, Qiaoshi,et al."Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation".CELL RESEARCH 27.6(2017):784-800.

入库方式： OAI收割

来源：上海药物研究所

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