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Critical role for mast cells in interleukin-1?-driven skin inflammation associated with an activating mutation in the nlrp3 protein.


ABSTRACT: Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1? (IL-1?) 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-1? in response to lipopolysaccharide or tumor necrosis factor-? (TNF-?). In neonatal mice, the microbiota induced TNF-? and IL-1? 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-1? in MCs. Surprisingly, neutralization of TNF-? abrogated IL-1? 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-1? production and skin inflammation in neonatal mice with the CAPS-associated Nlrp3 mutation.

SUBMITTER: Nakamura Y 

PROVIDER: S-EPMC3411177 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Critical role for mast cells in interleukin-1β-driven skin inflammation associated with an activating mutation in the nlrp3 protein.

Nakamura Yuumi Y   Franchi Luigi L   Kambe Naotomo N   Meng Guangxun G   Strober Warren W   Núñez Gabriel G  

Immunity 20120719 1


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 mi  ...[more]

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