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Immunity. 2012 Jul 27;37(1):85-95. doi: 10.1016/j.immuni.2012.04.013. Epub 2012 Jul 19.

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

Author information

1
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

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.

PMID:
22819042
PMCID:
PMC3411177
DOI:
10.1016/j.immuni.2012.04.013
[Indexed for MEDLINE]
Free PMC Article

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