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.
Highlights
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease to affect Caucasian populations
All inflammasomes were primed with lipopolysaccharide from Escherichia coli K12 (LPS), which targets TLR4 and is used to promote pro-IL-18/IL-1b expression; this was followed by stimulation with established activators of the inflammasomes, NLRC4, pyrin (TcdB) and AIM-2
When HBECs were stimulated with LPS, followed by ATP, a specific NLRP3 inflammasome activating signal that nucleates NLRP3 assembly with ASC, pyrin and caspase-1, IL-18 secretion was upregulated in Cystic Fibrosis (CF)-associated mutant cell lines, IB3-1 (p
Summary
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease to affect Caucasian populations. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in reduced expression and function of the CFTR with the most common mutation (DF508/DF508) resulting in inadequate processing of the protein and subsequent intracellular trapping in the endoplasmic reticulum (ER) (Elborn, 2016). Clinical manifestations of this debilitating condition include repeated pulmonary infections, innate immune-driven episodes of inflammation and inflammatory arthritis (Elborn, 2016; Whitsett and Alenghat, 2015; Bals et al, 1999; Montgomery et al, 2017).
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