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

TitlePropofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome
Authors
Keywordsanimal cell
apoptosis
BV-2 cell line
cell death
controlled study
Issue Date2019
PublisherNature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html
Citation
Cell Death & Disease, 2019, v. 10, p. article no. 542 How to Cite?
AbstractPropofol 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.
Persistent Identifierhttp://hdl.handle.net/10722/293259
ISSN
2019 Impact Factor: 6.304
2015 SCImago Journal Rankings: 2.484
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSun, L-
dc.contributor.authorMa, W-
dc.contributor.authorGao, W-
dc.contributor.authorXing, Y-
dc.contributor.authorChen, L-
dc.contributor.authorXia, Z-
dc.contributor.authorZhang, Z-
dc.contributor.authorDai, Z-
dc.date.accessioned2020-11-23T08:14:09Z-
dc.date.available2020-11-23T08:14:09Z-
dc.date.issued2019-
dc.identifier.citationCell Death & Disease, 2019, v. 10, p. article no. 542-
dc.identifier.issn2041-4889-
dc.identifier.urihttp://hdl.handle.net/10722/293259-
dc.description.abstractPropofol 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.-
dc.languageeng-
dc.publisherNature Publishing Group: Open Access Journals - Option C. The Journal's web site is located at http://www.nature.com/cddis/index.html-
dc.relation.ispartofCell Death & Disease-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectanimal cell-
dc.subjectapoptosis-
dc.subjectBV-2 cell line-
dc.subjectcell death-
dc.subjectcontrolled study-
dc.titlePropofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome-
dc.typeArticle-
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hk-
dc.identifier.authorityXia, Z=rp00532-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41419-019-1761-4-
dc.identifier.pmid31316052-
dc.identifier.pmcidPMC6637184-
dc.identifier.scopuseid_2-s2.0-85069457596-
dc.identifier.hkuros319854-
dc.identifier.volume10-
dc.identifier.spagearticle no. 542-
dc.identifier.epagearticle no. 542-
dc.identifier.isiWOS:000476590900002-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl2041-4889-

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