ENaC contributes to macrophage dysfunction in cystic fibrosis.

Cystic fibrosis (CF) is a chronic disease caused by dysfunctional or absent cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in immune cells and regulates innate immunity, both directly and indirectly. The epithelial sodium channel (ENaC) contributes to dysfunction in CF airway epithelial cells. However, the impact of non-CFTR ion channel dysfunction on CF immune responses is not understood. Improved understanding of how immune function is regulated by ion channels may allow antibiotic- and mutation-agnostic treatment approaches to chronic infection and inflammation. Therefore, we hypothesized that ENaC is aberrantly expressed in CF macrophages and directly contributes to impaired phagocytic and inflammatory functions. ENaC expression was characterized in immune cells isolated from CF and non-CF blood donors. Monocyte-derived macrophage (MDM) function and bacterial killing were tested with ENaC modulation. Baseline ENaC expression in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF and persisted after infection. CFTR inhibition in non-CF MDMs resulted in ENaC overexpression. CFTR modulator treatment reduced but did not eliminate ENaC overexpression in CF MDMs. Interestingly, ENaC inhibition increased CFTR expression. Amiloride-treated CF MDMs also showed normalized reactive oxygen species (ROS) production, improved autophagy, and decreased proinflammatory cytokine production. Sodium channel expression in CF MDMs normalized after amiloride treatment with minimal effect on other ion channels. In summary, ENaC modulation in immune cells is a novel potential therapeutic target for CF infection control, either in combination with CFTR modulators, or as a sole agent for people not eligible for CFTR modulators.NEW & NOTEWORTHY New research reveals that epithelial sodium channel (ENaC) overexpression in cystic fibrosis (CF) immune cells impairs macrophage function. Inhibiting ENaC increases cystic fibrosis transmembrane conductance regulator (CFTR) expression, normalizes reactive oxygen species production, improves autophagy, and reduces proinflammatory cytokine production. This suggests that ENaC modulation could be a novel therapeutic target for CF infection control, either alone or with CFTR modulators, offering new hope for patients not eligible for current treatments.