Lian Qiaoshi, Xu Jun, Yan Shanshan, Huang Min, Ding Honghua, Sun Xiaoyu, Bi Aiwei, Ding Jian, Sun Bing, Geng Meiyu
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Res. 2017 Jun;27(6):784-800. doi: 10.1038/cr.2017.54. Epub 2017 Apr 14.
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-1β 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.
化疗通常会引发严重的胃肠道毒性，但其潜在机制仍不清楚。本研究将广泛应用的细胞毒性药物伊立替康（CPT-11）作为代表性药物，并证明该治疗会导致肠道大量释放双链DNA，这是该化合物剂量限制性肠道毒性的原因。具体而言，通过外泌体分泌释放的“自身DNA”进入天然免疫细胞的细胞质并激活AIM2（黑色素瘤2中缺失）炎性小体。这会导致成熟的IL-1β和IL-18分泌，并引发肠道粘膜炎和迟发性腹泻。有趣的是，在AIM2缺陷小鼠中或通过沙利度胺等药理抑制剂消除AIM2信号，可显著降低药物性腹泻的发生率，而不影响CPT-11的抗癌疗效。这些发现为化疗如何触发导致肠道毒性的天然免疫反应提供了机制性见解，并揭示了维持抗肿瘤作用但规避相关不良炎症反应的新化疗方案。
