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Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation
Fahima Madouri1, Noëlline Guillou2, Louis Fauconnier3
1Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, F-45071 Orleans-Cedex2, France Artimmune SAS, 45100 Orléans, France.
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.
Insights
Caspase-1 activation and NLRP3 inflammasomes regulate house dust mite-induced allergic lung inflammation by modulating IL-33 levels. Absence of caspase-1 increases IL-33, worsening allergic responses.
Area of Science:
- Immunology
- Respiratory Medicine
- Inflammation Research
Background:
- Caspase-1 (Casp-1) is crucial for innate immunity via inflammasome activation.
- House dust mite (HDM) exposure triggers allergic airway inflammation.
- The role of Casp-1 in HDM-induced allergic lung inflammation requires elucidation.
Purpose of the Study:
- To investigate the regulatory role of caspase-1 activation in HDM-induced experimental allergic airway inflammation.
- To determine the involvement of specific inflammasome components, particularly NLRP3, in this process.
- To elucidate the mechanistic links between caspase-1, IL-33, and Th2 responses in allergic lung inflammation.
Main Methods:
- Comparative analysis of wild-type, caspase-1-deficient, and NLRP3-deficient mice exposed to HDM.
- Assessment of airway inflammation markers, including eosinophil recruitment and Th2 cytokine levels (IL-4, IL-5, IL-13).
- Evaluation of full-length and bioactive IL-33 expression, uric acid, and spleen tyrosine kinase (Syk) production.
- Intervention studies using IL-33 neutralization (soluble ST2 receptor) and recombinant IL-33 administration.
Main Results:
- Caspase-1-deficient mice exhibited enhanced airway inflammation, eosinophil recruitment, and elevated Th2 cytokines and IL-33 levels upon HDM exposure.
- NLRP3-deficient mice showed impaired control of eosinophil influx and increased Th2 responses, indicating NLRP3's role in controlling HDM-induced inflammation.
- Absence of caspase-1 correlated with increased IL-33, uric acid, and Syk production.
- IL-33 neutralization reduced allergic inflammation, while IL-33 administration exacerbated it in caspase-1-deficient mice.
Conclusions:
- Caspase-1, NLRP3, and ASC inflammasomes contribute to the regulation of HDM-induced allergic lung inflammation.
- Caspase-1 activation is critical for down-modulating IL-33 levels, thereby controlling Th2 responses in allergic airway inflammation.
- The NLRP3/ASC inflammasome complex plays a key role in regulating IL-33, impacting the severity of allergic lung inflammation.
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