Critical Role for Mast Cells in Interleukin-1β-Driven Skin Inflammation Associated with an Activating Mutation in the NIrp3 Protein

Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1 beta (IL-1 beta) 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 NIrp3 protein. Unlike normal cells, MCs expressing mutant NIrp3 produced IL-1 beta in response to lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha). In neonatal mice, the microbiota induced TNF-alpha and IL-1 beta and promoted skin disease. MC deficiency greatly reduced disease in NIrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1 beta in MCs. Surprisingly, neutralization of TNF-alpha abrogated IL-1 beta production and skin disease in neonatal NIrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1 beta production and skin inflammation in neonatal mice with the CAPS-associated NIrp3 mutation.