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

作　　者：Lian, Qiaoshi Xu, Jun Yan, Shanshan Huang, Min Ding, Honghua Sun, Xiaoyu Bi, Aiwei Ding, Jian Sun, Bing Geng, Meiyu[3] 

机构地区：[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

出　　处：《Cell Research》2017年第6期784-800,共17页细胞研究（英文版）

摘　　要：Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism re- mains 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 en- ters the cytosol of innate immune cells and activates the AIM2 （absent in melanoma 2） inflammasome. This leads to mature IL-Iβ 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 in- flammatory response.

关 键 词：DSDNA AIM2 EXOSOME INFLAMMASOME CHEMOTHERAPY intestinal toxicity 

分 类 号：Q523[生物学—生物化学] S852.2[农业科学—基础兽医学]