Critical Role for Mast Cells in Interleukin-1b-Driven Skin Inflammation Associated with an Activating Mutation in the Nlrp3 Protein

Yuumi Nakamura et al., Immunity. 2012, 37:85-95

Speaker: Ya-Ting Chu (朱雅婷)                                    Time: 15:10~16:00, Oct. 17, 2012

Commentator: Dr. Chiou-Feng Lin (林秋烽老師)       Place: Room 601

Abstract

The inflammasome is a molecular platform activated by pathogens or stress that drives the proteolytic activation of caspase-1. The activated caspase-1 cleaves pro-IL-1b and pro-IL-18 into their mature forms to engage innate immune defenses.   The NLRP1, NLRP3 and NLRC4inflammasomes belong to the intracellular Nod-like receptor (NLR) family. Recently, the important role of NLR molecules in inflammatory disease pathogenesis has been recognized. For example, a skin disease , cryopyrin-associated periodic syndromes (CAPS) is caused by a mutation in Nlrp3 gene that results in aberrant IL-1b production, but the mechanisms remain unclear. Previous study indicated that most of the IL-1b-positive cells in the skin lesions of CAPS patients are mast cells (MCs). In the present study, the authors used a mouse model to determine the roles of MCs and indigenous microbiota in mutant Nlrp3 gene induced skin disease. The results showed that MC deficiency in Nlrp3 mutant mice reduced the severity of skin disease. Unlike normal cells, the Nlrp3 mutant MCs induced activation of caspase-1 and production of IL-1b in response to LPS or TNF-a,but without the requirement for ATP. Furthermore, the authors found that indigenous microbiota was involved in TNF-a and IL-1b production and the development of skin disease in neonatal Nlrp3 mutant mice. Treatment with TNF-a blocking antibodies or antibiotics reduced IL-1b production and the development of skin disease in neonatal, but not in diseased adult Nlrp3 mutant mice. These findings were consistent with a previous study which indicated that treatment with IL-1b neutralizing antibodies was more effective than TNF-a blocking antibodies in reducing inflammatory disease in adult Nlrp3 mutant mice. Therefore, MCs and microbiota initiate TNF-a production leading to overproduction of IL-1b and the development of skin disease in neonatal CAPS -associated Nlrp3 mutant mice.

References

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2. Guangxun Meng. et al. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity. 30, 860-74 (2009).