Enhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model

Tran, H.B.Macowan, M.G.Abdo, A.Donnelley, M.Parsons, D.Hodge, S.2020-06-242020-06-242020Journal of Inflammation, 2020; 17(1):16-161476-92551476-9255http://hdl.handle.net/2440/126184Background:Inflammasomes and sphingosine-1-phosphate (S1P) signalling are increasingly subject to intensive research in human diseases. We hypothesize that in respiratory muco-obstructive diseases, mucus obstruction enhances NLRP3 inflammasome activation and dysregulated S1P signalling. Methods:Lung tissues from mice overexpressing the beta-unit of the epithelial sodium channel (βENaC) and their littermate controls were examined by histology, immunofluorescence and confocal microscopy, followed by ImageJ quantitative analysis. Results:Lower airways in βENaC mice showed patchy patterns of mucus obstruction and neutrophil-dominant infiltrations. In contrast to a ubiquitous distribution of TNFα specks, significantly (p < 0.05) increased specks of bronchiolar NLRP3, IL-1β, and IgG in the βENaC mouse lungs were localized to the vicinity of mucus obstruction sites. Bright Spinster homologue 2 (SPNS2) at the epithelial apex and positive correlation with sphingosine kinase 1 (SPHK1) (R2 = 0.640; p < 0.001) supported the normal bronchial epithelium as an active generator of extracellular S1P. SPNS2 in βENaC mice was sharply reduced (38%, p < 0.05) and lost apical localization at sites of mucus obstruction. A significant (34%; p < 0.01) decrease in epithelial SPHK2 was also noted at mucus obstruction sites. Conclusion:These results support that mucus obstruction may enhance NLRP3 inflammasome activation and dysregulated S1P signaling.enCystic fibrosisInflammasomeMouse modelRespiratory muco-obstructive diseasesSphingosine-1 phosphateEnhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease modelJournal article100002096410.1186/s12950-020-00248-20005299551000022-s2.0-85084321898530651Tran, H.B. [0000-0002-9463-4033]Macowan, M.G. [0000-0001-7721-1349]Abdo, A. [0000-0002-6329-8954]Donnelley, M. [0000-0002-5320-7756]Parsons, D. [0000-0002-8775-3501] [0000-0003-1746-3290]Hodge, S. [0000-0002-3602-9927] [0000-0002-9401-298X]