Neutrophil-specific gain-of-function mutations in <i>Nlrp3</i> promote development of cryopyrin-associated periodic syndrome
Julien Stackowicz, Nicolas Gaudenzio, Nadine Serhan, Eva Conde, Ophélie Godon, Thomas Marichal, Philipp Starkl, Bianca Balbino, Axel Roers, Pierre Bruhns, Friederike Jönsson, Philippe Moguelet, Sophie Georgin‐Lavialle, Lori Broderick, Hal M. Hoffman, Stephen J. Galli, Laurent L. Reber
Abstract
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.