Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Sci Rep. 2018 Nov 20;8(1):17066. doi: 10.1038/s41598-018-35151-7.
Despite the addition of cystic fibrosis transmembrane conductance regulator (CFTR) modulators to the cystic fibrosis (CF) treatment regimen, patients with CF continue to suffer from chronic bacterial infections that lead to progressive respiratory morbidity. Host immunity, and macrophage dysfunction specifically, has an integral role in the inability of patients with CF to clear bacterial infections. We sought to characterize macrophage responses to CFTR modulator treatment as we hypothesized that there would be differential effects based on patient genotype. Human CF and non-CF peripheral blood monocyte-derived macrophages (MDMs) were analyzed for CFTR expression, apoptosis, polarization, phagocytosis, bacterial killing, and cytokine production via microscopy, flow cytometry, and ELISA-based assays. Compared to non-CF MDMs, CF MDMs display decreased CFTR expression, increased apoptosis, and decreased phagocytosis. CFTR expression increased and apoptosis decreased in response to ivacaftor or lumacaftor/ivacaftor therapy, and phagocytosis improved with ivacaftor alone. Ivacaftor restored CF macrophage polarization responses to non-CF levels and reduced Pseudomonas aeruginosa bacterial burden, but did not reduce other bacterial loads. Macrophage inflammatory cytokine production decreased in response to ivacaftor alone. In summary, ivacaftor and lumacaftor/ivacaftor have differential impacts on macrophage function with minimal changes observed in CF patients treated with lumacaftor/ivacaftor. Overall improvements in macrophage function in ivacaftor-treated CF patients result in modestly improved macrophage-mediated bacterial killing.
尽管在囊性纤维化 (CF) 的治疗方案中添加了囊性纤维化跨膜电导调节因子 (CFTR) 调节剂，但 CF 患者仍继续遭受慢性细菌感染，导致进行性呼吸发病率增加。宿主免疫，特别是巨噬细胞功能障碍，在 CF 患者无法清除细菌感染方面起着至关重要的作用。我们试图描述巨噬细胞对 CFTR 调节剂治疗的反应，因为我们假设根据患者的基因型会有不同的影响。通过显微镜、流式细胞术和基于 ELISA 的测定，分析了 CF 和非 CF 外周血单核细胞衍生的巨噬细胞 (MDM) 的 CFTR 表达、凋亡、极化、吞噬、杀菌和细胞因子产生。与非 CF MDM 相比，CF MDM 显示 CFTR 表达降低、凋亡增加和吞噬作用降低。伊伐卡托或卢美卡托/伊伐卡托治疗后 CFTR 表达增加，凋亡减少，而单独使用伊伐卡托可改善吞噬作用。伊伐卡托将 CF 巨噬细胞极化反应恢复到非 CF 水平，并降低铜绿假单胞菌的细菌负担，但不能降低其他细菌负荷。巨噬细胞炎症细胞因子的产生在单独使用伊伐卡托时减少。总之，伊伐卡托和卢美卡托/伊伐卡托对巨噬细胞功能有不同的影响，而用卢美卡托/伊伐卡托治疗的 CF 患者观察到的变化最小。伊伐卡托治疗的 CF 患者的巨噬细胞功能总体改善导致巨噬细胞介导的杀菌作用略有改善。
