Linkage of bacterial colonization of skin and the urticaria-like rash of NLRP3-mediated autoinflammatory syndromes through mast cell-derived TNF-α

As anti-cytokine therapies were developed for clinical use during the last decade, anti-IL-1 therapies have emerged as a highly effective treatment for cryopyrin-associated periodic syndromes (CAPSs), including the urticaria-like rash. Based on clinical observations, we hypothesized that NLPR3 activation and IL-1 beta production, in particular in mast cells (MCs), are important for the development of this eruption, due to the observation that CAPS patients have gain-of-function mutations in NLRP3 that result in unregulated excess levels of IL-1 beta. To further address our hypothesis, we employed gene-targeted mice carrying Nlrp3 mutations and found that signaling in MCs following bacterial colonization of skin is essential for IL-1 beta-dependent inflammation. Intradermal administration of a molecule that induces the release of granule-associated molecules from MCs showed that MCs and TNF-alpha were necessary for the inflammation in CAPS-mimicking mice. However, adult CAPS mice exhibited a persistent skin phenotype and did not respond to anti-TNF-alpha antibody, indicating that TNF-alpha is important only for the onset of the disease and is dispensable during the chronic phase of CAPS. Thus, in this review, we highlight our recent findings on how MCs play an important role, not only in ordinary urticaria, but also in the urticaria-like rash associated with NLRP3 mutations. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.