Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome

作者：Lingbin Sun, Wei Ma, Wenli Gao, Yanmei Xing, Lixin Chen, Zhengyuan Xia, Zhongjun Zhang, Zhongliang Dai · 发表于：Cell Death and Disease · 年份：2019 · DOI：10.1038/s41419-019-1761-4 · 被引用次数：290 · 研究领域：Inflammasome and immune disorders、Thermal Regulation in Medicine、Respiratory Support and Mechanisms

Abstract Propofol infusion syndrome (PRIS) is an uncommon life-threatening complication observed most often in patients receiving high-dose propofol. High-dose propofol treatment with a prolonged duration can damage the immune system. However, the associated molecular mechanisms remain unclear. An increasing number of clinical and experimental observations have demonstrated that tissue-resident macrophages play a critical role in immune regulation during anaesthesia and procedural sedation. Since the inflammatory response is essential for mediating propofol-induced cell death and proinflammatory reactions, we hypothesised that propofol overdose induces macrophage pyroptosis through inflammasomes. Using primary cultured bone marrow-derived macrophages, murine macrophage cell lines (RAW264.7, RAW-asc and J774) and a mouse model, we investigated the role of NLRP3 inflammasome activation and secondary pyroptosis in propofol-induced cell death. We found that high-dose propofol strongly cleaved caspase-1 but not caspase-11 and biosynthesis of downstream interleukin (IL)-1β and IL-18. Inhibition of caspase-1 activity blocks IL-1β production. Moreover, NLRP3 deletion moderately suppressed cleaved caspase-1 as well as the proportion of pyroptosis, while levels of AIM2 were increased, triggering a compensatory pathway to pyroptosis in NLRP3 -/- macrophages. Here, we show that propofol-induced mitochondrial reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation. Further...