NLRP3 Inflammasome Assembly in Neutrophils Is Supported by PAD4 and Promotes NETosis Under Sterile Conditions.

Autor:	Münzer P; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.; Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany.; Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States., Negro R; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States., Fukui S; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., di Meglio L; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States.; Laboratory of Vascular Translational Science, U1148 INSERM University of Paris, Paris, France., Aymonnier K; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.; Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States., Chu L; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Cherpokova D; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Gutch S; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Sorvillo N; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Shi L; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Magupalli VG; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States., Weber ANR; Department of Immunology, Interfaculty Institute of Cell Biology, University of Tübingen, Tübingen, Germany., Scharf RE; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.; Division of Experimental and Clinical Hemostasis, Hemotherapy, and Transfusion Medicine, and Hemophilia Comprehensive Care Center, Institute of Transplantation Diagnostics and Cell Therapy, Heinrich Heine University Medical Center, Düsseldorf, Germany., Waterman CM; Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States.; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States., Wu H; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States., Wagner DD; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.; Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 May 28; Vol. 12, pp. 683803. Date of Electronic Publication: 2021 May 28 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.683803
Abstrakt:	Neutrophil 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 . Competing Interests: DDW is on the Scientific Advisory Board of Neutrolis, a preclinical-stage biotech company focused on DNases. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Münzer, Negro, Fukui, di Meglio, Aymonnier, Chu, Cherpokova, Gutch, Sorvillo, Shi, Magupalli, Weber, Scharf, Waterman, Wu and Wagner.)
Databáze:	MEDLINE
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