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

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. Furthermore, apoptosis-associated speck-like protein (ASC) was found to mediate NLRP3 and AIM2 signalling and contribute to propofol-induced macrophage pyroptosis. In addition, our work shows that propofol-induced apoptotic initiator caspase (caspase-9) subsequently cleaved effector caspases (caspase-3 and 7), indicating that both apoptotic and pyroptotic cellular death pathways are activated after propofol exposure. Our studies suggest, for the first time, that propofol-induced pyroptosis might be restricted to macrophage through an NLRP3/ASC/caspase-1 pathway, which provides potential targets for limiting adverse reactions during propofol application. These findings demonstrate that propofol overdose can trigger cell death through caspase-1 activation and offer new insights into the use of anaesthetic drugs.

• Authors: Lingbin Sun, Wei Ma, Wenli Gao, Yanmei Xing, Lixin Chen, Zhengyuan Xia, Zhongjun Zhang, Zhongliang Dai
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 8 Pg. 542 (07 17 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31316052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CARD Signaling Adaptor Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nlrp3 protein, mouse
• PYCARD protein, human
• Pycard protein, mouse
• Casp1 protein, mouse
• Caspase 1
• Propofol

Topics

• Animals
• CARD Signaling Adaptor Proteins (metabolism)
• Caspase 1 (genetics, metabolism)
• Cell Survival (drug effects)
• Gene Knockout Techniques
• Humans
• Inflammasomes (metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Propofol (pharmacology)
• Pyroptosis (drug effects)
• RAW 264.7 Cells
• Signal Transduction (drug effects)
• THP-1 Cells
• Transfection