title: Critical role for mast cells in interleukin-1β-driven skin inflammation associated with an activating mutation in the nlrp3 protein.
abstract: Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1β (IL-1β) production induced by mutations in the NLRP3 protein in humans, but the mechanisms involved remain poorly understood. Using a mouse model, we show a role for the indigenous microbiota and mast cells (MCs) in skin disease associated with mutant Nlrp3 protein. Unlike normal cells, MCs expressing mutant Nlrp3 produced IL-1β in response to lipopolysaccharide or tumor necrosis factor-α (TNF-α). In neonatal mice, the microbiota induced TNF-α and IL-1β and promoted skin disease. MC deficiency greatly reduced disease in Nlrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1β in MCs. Surprisingly, neutralization of TNF-α abrogated IL-1β production and skin disease in neonatal Nlrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1β production and skin inflammation in neonatal mice with the CAPS-associated Nlrp3 mutation.
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Yuumi
authors: Y
authors: Nakamura
authors: Luigi
authors: L
authors: Franchi
authors: Naotomo
authors: N
authors: Kambe
authors: Guangxun
authors: G
authors: Meng
authors: Warren
authors: W
authors: Strober
authors: Gabriel
authors: G
authors: Núñez
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000378:metabolism; D003872:Dermatitis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D005260:Female; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012871:Skin Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1