Excessive ENaC-mediated sodium influx drives NLRP3 inflammasome-dependent autoinflammation in cystic fibrosis

Abstract

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-1, ASCspecks 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 -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. Philip Hopkins (Leeds) for instrumental strategic support. Salvesen GS, Morris LX et al. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526: 666-71 Keiser NW, Birket SE, Evans IA, Tyler SR, Crooke AK, Sun X, Zhou W, Nellis JR, Stroebele EK, Chu KK, Tearney GJ, Stevens MJ, Harris JK, Rowe SM, Engelhardt JF (2015) Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulatorknockout ferret lungs. Am J Respir Cell Mol Biol 52: 683-94 Kelly B, O'Neill LAJ (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Research 25:

Differential Expressed Genes and Pathways Associated with Disease Severity In Siblings with Cystic Fibrosis

“…29 This finding supported the formation of the inflamasomme mechanism in nasal epithelial cells. 29,30 The decrease in the expression of genes in this pathway in severe patients could be elucidated by the decreased CFTR expression and ER stress.…”

Anti-Inflammatory Effects of RTD-1 in a Murine Model of Chronic Pseudomonas aeruginosa Lung Infection: Inhibition of NF-κB, Inflammasome Gene Expression, and Pro-IL-1β Biosynthesis

“…Results of in vivo and in vitro studies indicate that IL-1Ra, an inhibitory protein of various IL-1-related immune responses, can mitigate the damaging effects caused by chronic bacterial colonization [ 46 , 47 , 48 ]. Inhibition of IL-1β via antibody neutralization [ 43 ], small molecule NLRP3 inhibitors including MCC950 [ 40 ], inhibition of the epithelial sodium channel-NLRP3 axis [ 49 ], or by the IL-1Ra agonist Anakinra [ 46 ], ameliorates inflammasome-associated inflammation in models of CF via negative regulation of pathogenic NLRP3 activity. The results of these studies suggest that P. aeruginosa exploits the NLRP3 inflammasome pathway to evade immune cell killing and that this characteristic can be used as a therapeutic target.…”

Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies

“…This mucus then acts as a barrier for the delivery of drugs either into the mucus layer itself or across it to the airway epithelial cells [62]. Additionally, attainment of homeostasis of the imbalanced fluid and ions leads to the activation of inflammatory responses, primarily the NLRP3 inflammasome [65]. Thus, the accumulation of the thickened mucus inside the airways and the difficulty in its clearance, as well as the chronic bacterial infection and inflammation could contribute to the destruction of the lung and the respiratory failure in CF patients [62].…”