PT  - JOURNAL ARTICLE
AU  - Thomas Scambler
AU  - Heledd H. Jarosz-Griffiths
AU  - Samuel Lara-Reyna
AU  - Shelly Pathak
AU  - Chi Wong
AU  - Jonathan Holbrook
AU  - Fabio Martinon
AU  - Sinisa Savic
AU  - Daniel Peckham
AU  - Michael F. McDermott
TI  - Excessive ENaC-mediated sodium influx drives NLRP3 inflammasome-dependent autoinflammation in cystic fibrosis
AID  - 10.1101/458208
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 458208
4099  - http://biorxiv.org/content/early/2018/11/06/458208.short
4100  - http://biorxiv.org/content/early/2018/11/06/458208.full
AB  - Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and results in defective CFTR-mediated chloride transport, dysregulation of epithelial sodium channels (ENaC) and exaggerated innate immune responses. We tested the hypothesis that upregulation of ENaC drives autoinflammation in this complex monogenic disease.We show that monocytes from patients with CF exhibit a systemic proinflammatory cytokine signature, with associated anti-inflammatory M2-type macrophage deficiency. Cells harboring CF mutations are hyperresponsive to NLRP3 stimulation, as evidenced by increased IL-18, IL-1β, ASC-specks levels in serum and caspase-1 activity in monocytes, and by increased IL-18 production and caspase-1 activity in human bronchial epithelial cells (HBECs). In both cell types there is an associated shift to glycolytic metabolism with succinate release, in response to increased energy requirements. Inhibition of amiloride-sensitive sodium channels partially reverses the NLRP3-dependent inflammation and metabolic shift in these cells. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increases NLRP3-dependent inflammation, indicating a CFTR-independent ENaC axis in CF pathophysiology. Sodium channel modulation provides an important therapeutic strategy to combat lung inflammation in CF.