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.

Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis

“…As IL-1α is constitutively active, it can be released directly from necrotic cells in the airway epithelium (9) or actively secreted following activation of the NLRP3 inflammasome and caspase-1 (34,35) which is required for IL-1β cleavage and release. Activation of the NLRP3 inflammasome has been reported following RV infection resulting from calcium flux resulting from RV ion channel protein 2B activity (36), potassium efflux from lytic cell death such as necrosis or pyroptosis (37), and dysregulated sodium transport due to ENaC upregulation (38). It has also been observed in other inflammatory respiratory diseases with RV associated exacerbations as a hallmark of disease like asthma or COPD, where viral-induced cell death likely contributes to morbidity (36,39,40).…”

Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/ NLRP3 signaling in rat

“…Among these, NLRP3 inflammasome is involved in the onset and progression of several diseases [42]. It is composed of NLRP3 protein, adaptor protein apoptosisrelated speckles (ASC), and procaspase-1 [43,44]. The activation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1 and catalyzes the exudation of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, causing an inflammatory response [45,46].…”

Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/ NLRP3 signaling in rat

“…Among these, NLRP3 inflammasome is involved in the onset and progression of several diseases [47]. It is composed of NLRP3 protein, adaptor protein apoptosis-related speckles (ASC), and procaspase-1 [48,49]. The activation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1 and catalyzes the exudation of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, causing an inflammatory response [50,51].…”