ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

Research output: Contribution to journalArticlepeer-review

Authors

  • Thomas Scambler
  • Heledd H Jarosz-Griffiths
  • Samuel Lara-Reyna
  • Shelly Pathak
  • Chi Wong
  • And 5 others
  • Jonathan Holbrook
  • Fabio Martinon
  • Sinisa Savic
  • Daniel Peckham
  • Michael F McDermott

External organisations

  • University of Leeds

Abstract

Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.

Bibliographic note

© 2019, Scambler et al.

Details

Original languageEnglish
JournaleLife
Volume8
Publication statusPublished - 18 Sep 2019
Externally publishedYes

Keywords

  • Cell Line, Cystic Fibrosis/pathology, Epithelial Sodium Channels/metabolism, Humans, Immunity, Innate, Inflammation/pathology, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Sodium/metabolism