Moran John, Pugh Courtney, Brown Nevian, Thomas Ashley, Zhang Shuzhong, McCauley Emily, Cephas Amelia, Shrestha Chandra L, Partida-Sanchez Santiago, Bai Shasha, Bruscia Emanuela, Kopp Benjamin T
Center for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University, Atlanta, Georgia, United States.
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Jul 1;329(1):L61-L69. doi: 10.1152/ajplung.00009.2025. Epub 2025 Jun 2.
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 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.
囊性纤维化（CF）是一种由功能失调或缺失的囊性纤维化跨膜传导调节因子（CFTR）引起的慢性疾病。CFTR在免疫细胞中表达，并直接或间接地调节先天免疫。上皮钠通道（ENaC）导致CF气道上皮细胞功能障碍。然而，非CFTR离子通道功能障碍对CF免疫反应的影响尚不清楚。更好地了解离子通道如何调节免疫功能，可能会带来针对慢性感染和炎症的抗生素及突变无关的治疗方法。因此，我们假设ENaC在CF巨噬细胞中异常表达，并直接导致吞噬和炎症功能受损。在从CF和非CF献血者分离的免疫细胞中对ENaC表达进行了表征。通过ENaC调节测试了单核细胞衍生巨噬细胞（MDM）的功能和细菌杀伤能力。相对于非CF，人CF MDM、淋巴细胞和粒细胞中的基线ENaC表达在转录本和蛋白质水平均增加，并且在感染后持续存在。非CF MDM中的CFTR抑制导致ENaC过表达。CFTR调节剂治疗减少但未消除CF MDM中的ENaC过表达。有趣的是，ENaC抑制增加了CFTR表达。用阿米洛利处理的CF MDM也显示活性氧（ROS）产生正常化、自噬改善以及促炎细胞因子产生减少。用阿米洛利处理后，CF MDM中的钠通道表达正常化，对其他离子通道的影响最小。总之，免疫细胞中的ENaC调节是CF感染控制的一个新的潜在治疗靶点，可与CFTR调节剂联合使用，或作为不符合CFTR调节剂治疗条件的人的单一药物。新研究表明，囊性纤维化（CF）免疫细胞中上皮钠通道（ENaC）的过表达会损害巨噬细胞功能。抑制ENaC可增加囊性纤维化跨膜传导调节因子（CFTR）的表达，使活性氧产生正常化，改善自噬，并减少促炎细胞因子的产生。这表明ENaC调节可能是CF感染控制的一个新的治疗靶点，单独使用或与CFTR调节剂联合使用，为不符合当前治疗条件的患者带来新希望。
