Oct 31, 2018

Excessive ENaC-mediated sodium influx drives NLRP3 inflammasome-dependent autoinflammation in Cystic Fibrosis

BioRxiv : the Preprint Server for Biology
Michael McDermottSinisa Savic


Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting 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 bronchial epithelial cells (BECs). 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 pathophys...Continue Reading

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Mentioned in this Paper

Metabolic Process, Cellular
Immune Response
Axis Specification
Cystic-fibrosis Membrane-conductance-regulating Protein Activity
Cratoxylum formosum
Bronchial System
ASIC2 protein, human
Recombinant Interleukin-18
Interleukin-18 Production

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