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

Research output: Contribution to journalArticlepeer-review

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ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis. / Scambler, Thomas; Jarosz-Griffiths, Heledd H; Lara-Reyna, Samuel; Pathak, Shelly; Wong, Chi; Holbrook, Jonathan; Martinon, Fabio; Savic, Sinisa; Peckham, Daniel; McDermott, Michael F.

In: eLife, Vol. 8, 18.09.2019.

Research output: Contribution to journalArticlepeer-review

Harvard

Scambler, T, Jarosz-Griffiths, HH, Lara-Reyna, S, Pathak, S, Wong, C, Holbrook, J, Martinon, F, Savic, S, Peckham, D & McDermott, MF 2019, 'ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis', eLife, vol. 8. https://doi.org/10.7554/eLife.49248

APA

Scambler, T., Jarosz-Griffiths, H. H., Lara-Reyna, S., Pathak, S., Wong, C., Holbrook, J., Martinon, F., Savic, S., Peckham, D., & McDermott, M. F. (2019). ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis. eLife, 8. https://doi.org/10.7554/eLife.49248

Vancouver

Scambler T, Jarosz-Griffiths HH, Lara-Reyna S, Pathak S, Wong C, Holbrook J et al. ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis. eLife. 2019 Sep 18;8. https://doi.org/10.7554/eLife.49248

Author

Scambler, Thomas ; Jarosz-Griffiths, Heledd H ; Lara-Reyna, Samuel ; Pathak, Shelly ; Wong, Chi ; Holbrook, Jonathan ; Martinon, Fabio ; Savic, Sinisa ; Peckham, Daniel ; McDermott, Michael F. / ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis. In: eLife. 2019 ; Vol. 8.

Bibtex

@article{031909cc5eed4ce19cbdfa399765cd38,
title = "ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis",
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.",
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",
author = "Thomas Scambler and Jarosz-Griffiths, {Heledd H} and Samuel Lara-Reyna and Shelly Pathak and Chi Wong and Jonathan Holbrook and Fabio Martinon and Sinisa Savic and Daniel Peckham and McDermott, {Michael F}",
note = "{\textcopyright} 2019, Scambler et al.",
year = "2019",
month = sep,
day = "18",
doi = "10.7554/eLife.49248",
language = "English",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

RIS

TY - JOUR

T1 - ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

AU - Scambler, Thomas

AU - Jarosz-Griffiths, Heledd H

AU - Lara-Reyna, Samuel

AU - Pathak, Shelly

AU - Wong, Chi

AU - Holbrook, Jonathan

AU - Martinon, Fabio

AU - Savic, Sinisa

AU - Peckham, Daniel

AU - McDermott, Michael F

N1 - © 2019, Scambler et al.

PY - 2019/9/18

Y1 - 2019/9/18

N2 - 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.

AB - 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.

KW - Cell Line

KW - Cystic Fibrosis/pathology

KW - Epithelial Sodium Channels/metabolism

KW - Humans

KW - Immunity, Innate

KW - Inflammation/pathology

KW - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

KW - Sodium/metabolism

U2 - 10.7554/eLife.49248

DO - 10.7554/eLife.49248

M3 - Article

C2 - 31532390

VL - 8

JO - eLife

JF - eLife

SN - 2050-084X

ER -