Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation
Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation
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DOI：
10.1038/cr.2017.54
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发表时间：
2017-06-01
期刊：
影响因子：
44.1
通讯作者：
Geng, Meiyu
中科院分区：
文献类型：
--
作者：
Lian, Qiaoshi;Xu, Jun;Geng, Meiyu
众所周知，化疗通常会引起严重的胃肠道毒性，但其潜在机制仍不清楚。这项研究以广泛应用的细胞毒性药物伊立替康 (CPT-11) 作为代表药物，并证明治疗会诱导肠道中双链 DNA 的大量释放，从而解释了该化合物的剂量限制性肠道毒性。具体来说，通过外泌体分泌释放的“自身DNA”进入先天免疫细胞的胞质溶胶并激活AIM2（黑色素瘤2中不存在）炎性体。这导致成熟的IL-1β和IL-18分泌并诱发肠粘膜炎和迟发性腹泻。有趣的是，无论是在 AIM2 缺陷小鼠中还是通过沙利度胺等药物抑制剂来消除 AIM2 信号传导，都可以显着降低药物引起的腹泻的发生率，而不影响 CPT-11 的抗癌功效。这些发现为化疗如何触发先天免疫反应导致肠道毒性提供了机制见解，并揭示了新的化疗方案，可以维持抗肿瘤作用，但规避相关的不良炎症反应。
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.