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

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.

Caspase-1: an integral regulator of innate immunity

“…Furthermore, caspase-1-mediated cleavage of IL-33 after residue Asp 178 was shown to result in its inactivation [72]. In line with this data, Madouri and colleagues describe a regulatory role for caspase-1 in IL-33 signaling in vivo [37]. Following house dust mite (HDM)-induced experimental allergic airway inflammation, caspase-1 is activated and caspase-1 knockout mice exhibit enhanced airway inflammation with a marked eosinophil recruitment and increased expression of Th2 cytokines and chemokines when compared to wild-type (wt) mice.…”

“…Therefore, not only caspase-1 expression but also NLRP3/ASC-mediated caspase-1 activation seems to be required for the regulation of HDM-induced airway inflammation. Activated caspase-1 dampens IL-33 mRNA expression and IL-33 protein levels in the lungs, thereby regulating the HDM-induced allergic response [37]. Furthermore, absence of caspase-1 was associated with increased expression of uric acid and spleen tyrosine kinase, both known to be involved in the induction of type-2 immunity [37,73].…”

“…Activated caspase-1 dampens IL-33 mRNA expression and IL-33 protein levels in the lungs, thereby regulating the HDM-induced allergic response [37]. Furthermore, absence of caspase-1 was associated with increased expression of uric acid and spleen tyrosine kinase, both known to be involved in the induction of type-2 immunity [37,73]. Blockade of IL-33 signaling reduced the development of Th2 immunity following HDM immunization in caspase-1 knockout mice, emphasizing IL-33 as main target for the NLRP3/caspase-1-mediated regulation of HDMinduced experimental allergic airway inflammation.…”

“…However, increasing evidence suggests that active caspase-1 also accomplishes anti-inflammatory tasks [33][34][35][36][37][38][39]. Furthermore, enzymatically defective caspase-1 can serve as proinflammatory scaffold and rare occurring human variants of CASP1 with decreased or absent enzymatic activity are associated with recurrent febrile episodes [40,41].…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…128 It is also noted that caspase-1, in spite of its essential role in the assembly of NLRP3 inflammasome, is found to play a critical regulatory role in house dust mite-induced allergic lung inflammation through downregulation of IL-33. 129 Recent studies have identified a key role of autophagy in activation of the NLRP3 inflammasome. [130][131][132][133] Autophagy acts as a negative regulator of NLRP3 inflammasome activation through various mechanisms, including direct inhibition of NLRP3 inflammasome activation by removing sources of endogenous NLRP3 inflammasome agonists, such as damaged mitochondria and mitochondrial DNA, 62,69,132 suppression of IL-1b secretion by targeting pro-IL-1b for lysosomal degradation, 134 and selective degradation of inflammasome components, such as NLRP3 and ASC.…”