Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria

Urticarial rash observed in cryopyrin-associated periodic syndrome (CAPS) caused by nucleotide-binding oligomerization domain-leucine-rich repeats containing pyrin domain 3 (NLRP3) mutations is effectively suppressed by anti-interleukin (IL)-1 treatment, suggesting a pathophysiological role of IL-1. in the skin. However, the cellular mechanisms regulating IL-1. production in the skin of CAPS patients remain unclear. We identified mast cells (MCs) as the main cell population responsible for IL-1. production in the skin of CAPS patients. Unlike normal MCs that required stimulation with proinflammatory stimuli for IL-1. production, resident MCs from CAPS patients constitutively produced IL-1 beta. Primary MCs expressed inflammasome components and secreted IL-1. via NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain when stimulated with microbial stimuli known to activate caspase-1. Furthermore, MCs expressing disease-associated but not wild-type NLRP3 secreted IL-1. and induced neutrophil migration and vascular leakage, the histological hallmarks of urticarial rash, when transplanted into mouse skin. Our findings implicate MCs as IL-1. producers in the skin and mediators of histamine-independent urticaria through the NLRP3 inflammasome.