Caspase-1 deficiency reduces eosinophilia and interleukin-33 in an asthma exacerbation model

Abstract

Rhinovirus infections are common triggers of asthma exacerbations. Viruses can activate the inflammasome, resulting in processing and activation of caspase-1. This recruitment triggers production of interleukin (IL)-1β and IL-18, which have been implicated in asthma. Elucidating the involvement of the inflammasome and its compartments, such as caspase-1, in asthma exacerbations is warranted.Gene expression of caspase-1 was measured in rhinovirus-infected primary bronchial epithelial cells of asthmatic and healthy donors 24 h post-infection. In an in vivo exacerbation experiment C57BL/6 wild-type and caspase-1-/- mice were challenged with house dust mite followed by exposures to the viral mimic poly(I:C). General lung inflammatory parameters and levels of T-helper type 2 (Th2)-upstream cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 were assessed.Caspase-1 expression was elevated after rhinoviral infection exclusively in bronchial epithelial cells from asthmatics. In a translational mouse model of asthma exacerbation effects of caspase-1 on airway inflammation and Th2-upstream cytokines were explored. Caspase-1 deficient mice exhibited no alterations of general lung inflammatory parameters, but showed markedly reduced eosinophilia. Furthermore, the Th2-upstream cytokines IL-33, TSLP and IL-25 were reduced at exacerbation in mice lacking caspase-1.Rhinovirus infection increases bronchial epithelial caspase-1 in asthma. Caspase-1 may induce production of lung Th2-upstream cytokines and eosinophilia at exacerbations. Further targeting of caspase-1 signalling is warranted to explore its role in asthma exacerbations.

NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation

“…The authors found that caspase-1 restrained expression of cleaved IL-33 and that up-regulation of airway inflammation in Casp1 −/− mice correlated with higher bioactive IL-33 expression and increased lung infiltration of eosinophils [ 191 ]. In contrast to this study, lack of caspase-1 reduced eosinophilia and mature bioactive lung IL-33 levels in an asthma exerbation model [ 192 ]. Another study showed that IL-33 treatment reduced NLRP3 inflammasome activation and IL-1β production in microglia and intracerebral monocytes in experimental cerebral malaria thereby ameliorating pathology in the brain [ 193 ].…”

DUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus through Interleukin-1β Signaling

“…Rhinoviral infection of PBECs is known to activate the NLRP3 and NLRC5 inflammasomes, leading to IL-1β release (26, 52). More recently, RV infection was found to increase caspase 1 expression to a greater extent in asthmatic PBECs than in normal cells, and in a house dust mite murine model of asthma exacerbations, caspase 1 knockout mice had reduced Th2 responses to poly(I:C) (53). Thus, a potential role of DUSP10 in regulating the inflammasome has significant implications for asthma.…”

Pyroptosis versus necroptosis: similarities, differences, and crosstalk

“…However, LPS-induced lethality is reduced in IL-33-deficient mice [112] implying that IL-33 may contribute to the pyroptotic-generated inflammatory response. Nonetheless, in other inflammatory models, such as allergic asthma, caspase-1 has been reported to either limit [161], or increase [162], IL-33 levels.…”