Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation

Fahima Madouri, Noëlline Guillou, Louis Fauconnier, Tiffany Marchiol, Nathalie Rouxel, Pauline Chenuet, Aurélie Ledru, Lionel Apetoh, François Ghiringhelli, Mathias Chamaillard, Song Guo Zheng, Fabrice Trovero, Valérie F.J. Quesniaux, Bernhard Ryffel, Dieudonnée Togbe

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

The cysteine protease caspase-1 (Casp-1) contributes to innate immunity through the assembly of NLRP3, NLRC4, AIM2, and NLRP6 inflammasomes. Here we ask whether caspase-1 activation plays a regulatory role in house dust mite (HDM)-induced experimental allergic airway inflammation. We report enhanced airway inflammation in caspase-1-deficient mice exposed to HDM with a marked eosinophil recruitment, increased expression of IL-4, IL-5, IL-13, as well as full-length and bioactive IL-33. Furthermore, mice deficient for NLRP3 failed to control eosinophil influx in the airways and displayed augmented Th2 cytokine and chemokine levels, suggesting that the NLPR3 inflammasome complex controls HDM-induced inflammation. IL-33 neutralization by administration of soluble ST2 receptor inhibited the enhanced allergic inflammation, while administration of recombinant IL-33 during challenge phase enhanced allergic inflammation in caspase-1-deficient mice. Therefore, we show that caspase-1, NLRP3, and ASC, but not NLRC4, contribute to the upregulation of allergic lung inflammation. Moreover, we cannot exclude an effect of caspase-11, because caspase-1-deficient mice are deficient for both caspases. Mechanistically, absence of caspase-1 is associated with increased expression of IL-33, uric acid, and spleen tyrosine kinase (Syk) production. This study highlights a critical role of caspase-1 activation and NLPR3/ASC inflammasome complex in the down-modulation of IL-33 in vivo and in vitro, thereby regulating Th2 response in HDM-induced allergic lung inflammation.

Original languageEnglish (US)
Pages (from-to)351-365
Number of pages15
JournalJournal of Molecular Cell Biology
Volume7
Issue number4
DOIs
StatePublished - Aug 1 2015

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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