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

J Mol Cell Biol. 2015 Aug;7(4):351-65. doi: 10.1093/jmcb/mjv012. Epub 2015 Feb 24.


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.

Keywords: IL-33; allergic asthma; caspase-1; house dust mite; inflammasomes; spleen tyrosine kinase (Syk); uric acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Antigens, Dermatophagoides / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / metabolism*
  • Caspase 1 / deficiency
  • Caspase 1 / metabolism*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Hypersensitivity / enzymology
  • Hypersensitivity / immunology*
  • Hypersensitivity / parasitology
  • Immunity / drug effects
  • Inflammasomes / metabolism*
  • Inflammation / complications
  • Inflammation / immunology*
  • Inflammation / pathology
  • Interleukin-33 / immunology*
  • Lung / enzymology
  • Lung / immunology*
  • Lung / parasitology
  • Lung / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pyroglyphidae / immunology*
  • Recombinant Fusion Proteins / pharmacology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology
  • Uric Acid / metabolism


  • Antigens, Dermatophagoides
  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-33
  • Ipaf protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Recombinant Fusion Proteins
  • Uric Acid
  • Caspase 1