Invited review article| Volume 71, ISSUE 2, P83-88, August 2013

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-1β 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-1β. 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-1β-dependent inflammation. Intradermal administration of a molecule that induces the release of granule-associated molecules from MCs showed that MCs and TNF-α 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-α antibody, indicating that TNF-α 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.


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      Naotomo Kambe obtained his MD degree from Gunma University (Maebashi, Japan) in 1994 and trained in dermatology. In 1998, he studied with Prof H. Matsuda at the Veterinary Clinic of Tokyo University of Agriculture and Technology (Fuchu, Japan), and obtained his Ph.D. degree from Gunma University in 1999. After two years working with Prof. L.B. Schwartz in the Rheumatology/Allergy division of Virginia Commonwealth University (Richmond, VA), he spent six years at Kyoto University (Kyoto, Japan) where he initiated studies on autoinflammatory diseases associated with mutated intracellular pattern recognition receptors. He has been at Chiba University (Chiba, Japan) since 2007. Recently he received JSID Award 2012.