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-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
Yuumi
Y
Department of Dermatology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
Kambe
Naotomo
N
Saito
Megumu
M
Nishikomori
Ryuta
R
Nishikomiri
Ryuta
R
Kim
Yun-Gi
YG
Murakami
Makoto
M
Núñez
Gabriel
G
Matsue
Hiroyuki
H
D000634:Aminoquinolines / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000276:immunology; D006632:Histamine / Q000276:immunology*; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008407:Mast Cells / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000502:physiology; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology*; D014581:Urticaria / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*
D000634:Aminoquinolines; D002352:Carrier Proteins; D007369:Interferon Inducers; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D006632:Histamine; D020169:Caspases; D000077271:Imiquimod