Frontiers in Immunology (May 2021)
NLRP3 Inflammasome Assembly in Neutrophils Is Supported by PAD4 and Promotes NETosis Under Sterile Conditions
- Patrick Münzer,
- Patrick Münzer,
- Patrick Münzer,
- Patrick Münzer,
- Roberto Negro,
- Roberto Negro,
- Shoichi Fukui,
- Shoichi Fukui,
- Lucas di Meglio,
- Lucas di Meglio,
- Lucas di Meglio,
- Karen Aymonnier,
- Karen Aymonnier,
- Karen Aymonnier,
- Long Chu,
- Long Chu,
- Deya Cherpokova,
- Deya Cherpokova,
- Sarah Gutch,
- Sarah Gutch,
- Nicoletta Sorvillo,
- Nicoletta Sorvillo,
- Lai Shi,
- Lai Shi,
- Venkat Giri Magupalli,
- Venkat Giri Magupalli,
- Alexander N. R. Weber,
- Rüdiger E. Scharf,
- Rüdiger E. Scharf,
- Rüdiger E. Scharf,
- Clare M. Waterman,
- Clare M. Waterman,
- Hao Wu,
- Hao Wu,
- Denisa D. Wagner,
- Denisa D. Wagner,
- Denisa D. Wagner,
- Denisa D. Wagner
Affiliations
- Patrick Münzer
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Patrick Münzer
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Patrick Münzer
- Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany
- Patrick Münzer
- Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States
- Roberto Negro
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Roberto Negro
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
- Shoichi Fukui
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Shoichi Fukui
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Lucas di Meglio
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Lucas di Meglio
- Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States
- Lucas di Meglio
- Laboratory of Vascular Translational Science, U1148 INSERM University of Paris, Paris, France
- Karen Aymonnier
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Karen Aymonnier
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Karen Aymonnier
- Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States
- Long Chu
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Long Chu
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Deya Cherpokova
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Deya Cherpokova
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Sarah Gutch
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Sarah Gutch
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Nicoletta Sorvillo
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Nicoletta Sorvillo
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Lai Shi
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Lai Shi
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Venkat Giri Magupalli
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Venkat Giri Magupalli
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
- Alexander N. R. Weber
- Department of Immunology, Interfaculty Institute of Cell Biology, University of Tübingen, Tübingen, Germany
- Rüdiger E. Scharf
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Rüdiger E. Scharf
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Rüdiger E. Scharf
- 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
- Clare M. Waterman
- Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States
- Clare M. Waterman
- Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States
- Hao Wu
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
- Denisa D. Wagner
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, United States
- Denisa D. Wagner
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States
- Denisa D. Wagner
- Whitman Center, Marine Biological Laboratory, Woods Hole, MA, United States
- Denisa D. Wagner
- 0Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2021.683803
- Journal volume & issue
-
Vol. 12
Abstract
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.
Keywords
