Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease

Abstract

Previous studies demonstrated spontaneous type 2 airway inflammation with eosinophilia juvenile Scnn1b-Tg mice with muco-obstructive lung disease. Interleukin-1 receptor (IL-1R) signaling has been implicated in allergen-driven airways disease, however, its role in eosinophilic inflammation in mucoobstructive lung disease remains unknown. In this study, we examined the role of IL-1R signaling in the development of airway eosinophilia and type 2 inflammation in juvenile Scnn1b-Tg mice. We determined effects of genetic deletion of Il1r1 on eosinophil counts, transcript levels of key type 2 cytokines, markers of eosinophil activation and apoptosis, and tissue morphology in lungs of Scnn1b-Tg mice at different time points during neonatal development. Further, we measured endothelial surface expression of intercellular adhesion molecule 1 (ICAM-1), an integrin involved in eosinophil transendothelial migration, and determined effects of eosinophil depletion using an anti-IL-5 antibody on lung morphology. Lack of IL-1R reduced airway eosinophilia and structural lung damage, but did not reduce levels of type 2 cytokines and associated eosinophil activation in Scnn1b-Tg mice. Structural lung damage in Scnn1b-Tg mice was also reduced by eosinophil depletion. Lack of IL-1R was associated with reduced expression of ICAM-1 on lung endothelial cells and reduced eosinophil counts in lungs from Scnn1b-Tg mice. We conclude that IL-1R signaling is implicated in airway eosinophilia independent of type 2 cytokines in juvenile Scnn1b-Tg mice. Our data suggest that IL-1R signaling may be relevant in the pathogenesis of eosinophilic airway inflammation in muco-obstructive lung diseases, which may, in part, be mediated by ICAM-1 dependent transmigration of eosinophils into the lungs.

Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis

“…It is therefore important to elucidate triggers of early inflammation prior to bacterial colonization of the CF airway. As IL-1R signaling has been investigated as a key pathway driving neutrophilic and eosinophilic inflammation in the airway (9,12,32,33), we next investigated IL-1α and IL-1β signaling following RV infection of AEC. As IL-1α is constitutively active, it can be released directly from necrotic cells in the airway epithelium (9) or actively secreted following activation of the NLRP3 inflammasome and caspase-1 (34,35) which is required for IL-1β cleavage and release.…”

Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice

“…In addition, IL-1 signalling has been implicated in structural lung damage in the βENaC-Tg model. Both genetic deletion and pharmacological targeting of the IL-1 receptor with anakinra reduced structural lung damage in βENaC-Tg mice [37,49]. Further studies analysing the involvement and interplay of other proteases, e.g., NE, MMP-12, as well as the IL-1 signalling pathway in βENaC-Tg mice with CatS knockdown will expand our understanding of the pathogenesis of the lung phenotype associated with this important mouse model.…”