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.
Highlights
Propofol is one of the most commonly used intravenous agents for anaesthesia and procedural sedation
A slightly increased level of tumour necrosis factor-α (TNF-α) (1.65-fold) compared to that of the control was noted with 600 μM treatment, while the level of MCP-1 was downregulated (Fig. 1g). These results demonstrated that the potentiated production of IL-1α, IL-1β and IL-18 was not due to a global inflammatory response but rather to the activation of caspase-1, which strongly suggested that propofol induces macrophage pyroptosis
We explored whether AIM2 or the NLR family is involved in macrophage pyroptosis induced by propofol and found that the levels of NLRP3 were significantly upregulated by propofol in a time- and dose-dependent manner
Summary
Propofol is one of the most commonly used intravenous agents for anaesthesia and procedural sedation. Propofol has many pharmacological advantages over other anaesthetic agents, side effects, including cardiac depression, hypotension and vomiting after propofol infusion, remain inevitable in the context of abuse, even at therapeutic doses, in the absence of medical assistance[1]. Among the adverse effects of propofol, immune. Sun et al Cell Death and Disease (2019)10:542 dysregulation has a prominent role[2,3]. High-dose propofol can result in a rare complication, in patients with acute neurological or inflammatory illnesses, which is known as propofol infusion syndrome (PRIS)[5,6,7]. Restricting the impacts of immune dysregulation after propofol application would be a promising strategy to reduce adverse effects. The mechanism underlying this immune dysregulation is still largely unknown
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