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

Hai B Tran; Matthew G Macowan; Adrian Abdo; Martin Donnelley; David Parsons; Sandra Hodge

doi:10.1186/s12950-020-00248-2

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

J Inflamm (Lond). 2020 Apr 21:17:16. doi: 10.1186/s12950-020-00248-2. eCollection 2020.

Authors

Hai B Tran^#^{1

2}, Matthew G Macowan^#^{1

2}, Adrian Abdo², Martin Donnelley^{2

3

4}, David Parsons^{2

3

4}, Sandra Hodge^{1

2}

Affiliations

¹ 1Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
² 2Adelaide Medical School, University of Adelaide, Adelaide, Australia.
³ 3Respiratory and Sleep Medicine, Women's and Children's Hospital, Adelaide, Australia.
⁴ 4Robinson Research Institute, University of Adelaide, Adelaide, Australia.

^# Contributed equally.

Abstract

Background: 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.

Keywords: Cystic fibrosis; Inflammasome; Mouse model; Respiratory muco-obstructive diseases; Sphingosine-1 phosphate.