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dc.contributor.authorMünzer, Patrick  Concept link
dc.contributor.authorNegro, Roberto  Concept link
dc.contributor.authorFukui, Shoichi  Concept link
dc.contributor.authordi Meglio, Lucas  Concept link
dc.contributor.authorAymonnier, Karen  Concept link
dc.contributor.authorChu, Long  Concept link
dc.contributor.authorCherpokova, Deya  Concept link
dc.contributor.authorGutch, Sarah  Concept link
dc.contributor.authorSorvillo, Nicoletta  Concept link
dc.contributor.authorShi, Lai  Concept link
dc.contributor.authorMagupalli, Venkat Giri  Concept link
dc.contributor.authorWeber, Alexander N. R.  Concept link
dc.contributor.authorScharf, Rüdiger E.  Concept link
dc.contributor.authorWaterman, Clare M.  Concept link
dc.contributor.authorWu, Hao  Concept link
dc.contributor.authorWagner, Denisa D.  Concept link
dc.date.accessioned2021-09-14T19:42:49Z
dc.date.available2021-09-14T19:42:49Z
dc.date.issued2021-03-28
dc.identifier.citationMuenzer, P., Negro, R., Fukui, S., di Meglio, L., Aymonnier, K., Chu, L., Cherpokova, D., Gutch, S., Sorvillo, N., Shi, L., Magupalli, V. G., Weber, A. N. R., Scharf, R. E., Waterman, C. M., Wu, H., & Wagner, D. D. (2021). NLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions. Frontiers in Immunology, 12, 683803.en_US
dc.identifier.urihttps://hdl.handle.net/1912/27548
dc.description© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Muenzer, P., Negro, R., Fukui, S., di Meglio, L., Aymonnier, K., Chu, L., Cherpokova, D., Gutch, S., Sorvillo, N., Shi, L., Magupalli, V. G., Weber, A. N. R., Scharf, R. E., Waterman, C. M., Wu, H., & Wagner, D. D. NLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditions. Frontiers in Immunology, 12, (2021): 683803, https://doi.org/10.3389/fimmu.2021.683803.en_US
dc.description.abstractNeutrophil extracellular trap formation (NETosis) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly are associated with a similar spectrum of human disorders. While NETosis is known to be regulated by peptidylarginine deiminase 4 (PAD4), the role of the NLRP3 inflammasome in NETosis was not addressed. Here, we establish that under sterile conditions the cannonical NLRP3 inflammasome participates in NETosis. We show apoptosis-associated speck-like protein containing a CARD (ASC) speck assembly and caspase-1 cleavage in stimulated mouse neutrophils without LPS priming. PAD4 was needed for optimal NLRP3 inflammasome assembly by regulating NLRP3 and ASC protein levels post-transcriptionally. Genetic ablation of NLRP3 signaling resulted in impaired NET formation, because NLRP3 supported both nuclear envelope and plasma membrane rupture. Pharmacological inhibition of NLRP3 in either mouse or human neutrophils also diminished NETosis. Finally, NLRP3 deficiency resulted in a lower density of NETs in thrombi produced by a stenosis-induced mouse model of deep vein thrombosis. Altogether, our results indicate a PAD4-dependent formation of the NLRP3 inflammasome in neutrophils and implicate NLRP3 in NETosis under noninfectious conditions in vitro and in vivo.en_US
dc.description.sponsorshipThis work was supported by a grant from National Heart, Lung, and Blood Institute of the National Institutes of Health (grant R35 HL135765) and a Steven Berzin family support to DDW, an Individual Erwin Deutsch fellowship by the German, Austrian and Swiss Society of Thrombosis and Hemostasis Research to RES, a Whitman fellowship (MBL) to DDW, and an Individual Marie Skłodowska-Curie Actions fellowship by the European Commission (796365 - COAGULANT) to PM. ANRW was funded by the Deutsche Forschungsgemeinschaft (TRR156/2 –246807620) and a research grant (We-4195/15-19). CMW was supported by the Division of Intramural Research, NHLBI, NIH.en_US
dc.publisherFrontiers Mediaen_US
dc.relation.urihttps://doi.org/10.3389/fimmu.2021.683803
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectNeutrophilsen_US
dc.subjectNETsen_US
dc.subjectNLRP3 inflammasomeen_US
dc.subjectMCC950en_US
dc.subjectdeep vein thrombosisen_US
dc.subjectPAD4en_US
dc.titleNLRP3 inflammasome assembly in neutrophils is supported by PAD4 and promotes NETosis under sterile conditionsen_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fimmu.2021.683803


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International