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ENaC contributes to macrophage dysfunction in cystic fibrosis
John Moran1, Courtney Pugh2, Nevian Brown2
1Center for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University, Atlanta, Georgia, United States.
Summary
Epithelial sodium channel (ENaC) is overexpressed in cystic fibrosis (CF) immune cells, impairing their function. Inhibiting ENaC in CF macrophages restores normal immune responses and may offer a new therapeutic strategy for CF infection control.
Area of Science:
- Immunology
- Cell Biology
- Respiratory Medicine
Background:
- Cystic fibrosis (CF) involves dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR).
- CFTR regulates innate immunity, but the role of other ion channels in CF immune dysfunction is unclear.
- Epithelial sodium channel (ENaC) is implicated in CF airway epithelial cell dysfunction.
Purpose of the Study:
- To investigate the hypothesis that ENaC is aberrantly expressed in CF macrophages and impairs immune functions.
- To explore ENaC modulation as a potential therapeutic target for CF infection and inflammation.
Main Methods:
- Characterized ENaC expression in immune cells from CF and non-CF donors.
- Assessed monocyte-derived macrophage (MDM) function and bacterial killing with ENaC modulation.
- Utilized CFTR inhibition and CFTR modulator treatments in experiments.
Main Results:
- Increased ENaC expression (transcript and protein) in CF MDMs, lymphocytes, and granulocytes.
- ENaC inhibition in CF MDMs normalized reactive oxygen species (ROS) production, improved autophagy, and reduced pro-inflammatory cytokines.
- ENaC inhibition increased CFTR expression, while CFTR modulator treatment partially reduced ENaC overexpression.
Conclusions:
- Aberrant ENaC expression in CF immune cells contributes to impaired phagocytic and inflammatory functions.
- ENaC modulation presents a novel therapeutic target for CF infection control, potentially complementing or replacing CFTR modulators.
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