PMA and crystal‐induced neutrophil extracellular trap formation involves RIPK1‐RIPK3‐MLKL signaling

Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside‐in signaling pathway triggering NET formation is unknown. Here, we show that the receptor‐interacting protein kinase (RIPK)‐1‐stabilizers necrostatin‐1 or necrostati...

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Bibliographic Details
Published in:European journal of immunology 2016-01, Vol.46 (1), p.223-229
Main Authors: Desai, Jyaysi, Kumar, Santhosh V., Mulay, Shrikant R., Konrad, Lukas, Romoli, Simone, Schauer, Christine, Herrmann, Martin, Bilyy, Rostyslav, Müller, Susanna, Popper, Bastian, Nakazawa, Daigo, Weidenbusch, Marc, Thomasova, Dana, Krautwald, Stefan, Linkermann, Andreas, Anders, Hans‐Joachim
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Extracellular Traps - immunology
Extracellular Traps - metabolism
Female
Humans
Kinases
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Necroptosis
Necrosis
Neutrophil
Neutrophil extracellular trap formation
Neutrophils
Neutrophils - immunology
Neutrophils - metabolism
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - toxicity
Polymethacrylic Acids - toxicity
Protein Kinases - immunology
Protein Kinases - metabolism
Receptor-Interacting Protein Serine-Threonine Kinases - immunology
Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
Receptor‐interacting protein kinase
Signal Transduction - immunology
Uric Acid - toxicity
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Summary:Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside‐in signaling pathway triggering NET formation is unknown. Here, we show that the receptor‐interacting protein kinase (RIPK)‐1‐stabilizers necrostatin‐1 or necrostatin‐1s and the mixed lineage kinase domain‐like (MLKL)‐inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal‐ or PMA‐induced NET formation in human and mouse neutrophils. These compounds do not affect PMA‐ or urate crystal‐induced production of ROS. Moreover, neutrophils of chronic granulomatous disease patients are shown to lack PMA‐induced MLKL phosphorylation. Genetic deficiency of RIPK3 in mice prevents MSU crystal‐induced NET formation in vitro and in vivo. Thus, neutrophil death and NET formation may involve the signaling pathway defining necroptosis downstream of ROS production. These data imply that RIPK1, RIPK3, and MLKL could represent molecular targets in gout or other crystallopathies.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201545605