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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-1beta in the skin. However, the cellular mechanisms regulating IL-1beta production in the skin of CAPS patients remain unclear. We identified mast cells (MCs) as the main cell population responsible for IL-1beta production in the skin of CAPS patients. Unlike normal MCs that required stimulation with proinflammatory stimuli for IL-1beta production, resident MCs from CAPS patients constitutively produced IL-1beta. Primary MCs expressed inflammasome components and secreted IL-1beta 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-1beta and induced neutrophil migration and vascular leakage, the histological hallmarks of urticarial rash, when transplanted into mouse skin. Our findings implicate MCs as IL-1beta producers in the skin and mediators of histamine-independent urticaria through the NLRP3 inflammasome.
Nakamura et al. (Mon,) studied this question.