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
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
ER -