Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome

Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as "cryopyrin-associated periodic syndromes" (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1β...

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Veröffentlicht in:The Journal of experimental medicine 2021-10, Vol.218 (10)
Hauptverfasser: Stackowicz, Julien, Gaudenzio, Nicolas, Serhan, Nadine, Conde, Eva, Godon, Ophélie, Marichal, Thomas, Starkl, Philipp, Balbino, Bianca, Roers, Axel, Bruhns, Pierre, Jönsson, Friederike, Moguelet, Philippe, Georgin-Lavialle, Sophie, Broderick, Lori, Hoffman, Hal M, Galli, Stephen J, Reber, Laurent L
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Sprache:eng
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Zusammenfassung:Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as "cryopyrin-associated periodic syndromes" (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20201466