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

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dc.contributor.authorTran, H.B.
dc.contributor.authorMacowan, M.G.
dc.contributor.authorAbdo, A.
dc.contributor.authorDonnelley, M.
dc.contributor.authorParsons, D.
dc.contributor.authorHodge, S.
dc.date.issued2020
dc.description.abstractBackground: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.
dc.identifier.citationJournal of Inflammation, 2020; 17(1):16-16
dc.identifier.doi10.1186/s12950-020-00248-2
dc.identifier.issn1476-9255
dc.identifier.issn1476-9255
dc.identifier.orcidTran, H.B. [0000-0002-9463-4033]
dc.identifier.orcidMacowan, M.G. [0000-0001-7721-1349]
dc.identifier.orcidAbdo, A. [0000-0002-6329-8954]
dc.identifier.orcidDonnelley, M. [0000-0002-5320-7756]
dc.identifier.orcidParsons, D. [0000-0002-8775-3501] [0000-0003-1746-3290]
dc.identifier.orcidHodge, S. [0000-0002-3602-9927] [0000-0002-9401-298X]
dc.identifier.urihttp://hdl.handle.net/2440/126184
dc.language.isoen
dc.publisherBMC
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/626863
dc.source.urihttps://doi.org/10.1186/s12950-020-00248-2
dc.subjectCystic fibrosis
dc.subjectInflammasome
dc.subjectMouse model
dc.subjectRespiratory muco-obstructive diseases
dc.subjectSphingosine-1 phosphate
dc.titleEnhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model
dc.typeJournal article
pubs.publication-statusPublished

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