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

被引:106
作者
Muenzer, Patrick [1 ,2 ,3 ,4 ]
Negro, Roberto [1 ,5 ]
Fukui, Shoichi [1 ,2 ]
di Meglio, Lucas [1 ,4 ,6 ]
Aymonnier, Karen [1 ,2 ,4 ]
Chu, Long [1 ,2 ]
Cherpokova, Deya [1 ,2 ]
Gutch, Sarah [1 ,2 ]
Sorvillo, Nicoletta [1 ,2 ]
Shi, Lai [1 ,2 ]
Magupalli, Venkat Giri [1 ]
Weber, Alexander N. R. [7 ]
Scharf, Rudiger E. [1 ,2 ,8 ,9 ]
Waterman, Clare M. [10 ]
Wu, Hao [1 ,5 ]
Wagner, Denisa D. [1 ,2 ,4 ,11 ]
机构
[1] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
[2] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA
[3] Univ Tubingen, Dept Cardiol & Angiol, Tubingen, Germany
[4] Marine Biol Lab, Whitman Ctr, Woods Hole, MA 02543 USA
[5] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[6] Univ Paris, INSERM, U1148, Lab Vasc Translat Sci, Paris, France
[7] Univ Tubingen, Interfac Inst Cell Biol, Dept Immunol, Tubingen, Germany
[8] Heinrich Heine Univ, Med Ctr, Div Expt & Clin Hemostasis Hemotherapy & Transfus, Dusseldorf, Germany
[9] Heinrich Heine Univ, Med Ctr, Hemophilia Comprehens Care Ctr, Inst Transplantat Diagnost & Cell Therapy, Dusseldorf, Germany
[10] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA
[11] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA
来源
FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷
基金
美国国家卫生研究院;
关键词
Neutrophils; NETs; NLRP3; inflammasome; MCC950; deep vein thrombosis; PAD4; DEEP-VEIN THROMBOSIS; PEPTIDYLARGININE DEIMINASE 4; CHROMATIN DECONDENSATION; ADAPTER ASC; CELL-DEATH; ACTIVATION; SECRETION; CLEAVAGE; INJURY; TRAPS;
D O I
10.3389/fimmu.2021.683803
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
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页数:16
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