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

作者：Thomas Scambler, Heledd Jarosz-Griffiths, Samuel J Lara Reyna, Shelly Pathak, Chi Huey Wong, Jonathan A. Holbrook, Fabio Martinon, Sinisa Savic, Daniel Gavin Peckham, Michael McDermott · 发表于：eLife · 年份：2019 · DOI：10.7554/elife.49248 · 被引用次数：107 · 研究领域：Inflammasome and immune disorders、Pediatric health and respiratory diseases、IL-33, ST2, and ILC Pathways

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.