Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have differential effects on cystic fibrosis macrophage
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have differential effects on cystic fibrosis macrophage
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DOI：
10.1038/s41598-018-35151-7
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发表时间：
2018-11-20
影响因子：
4.6
通讯作者：
Kopp, Benjamin T.
中科院分区：
文献类型：
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作者：
Zhang, Shuzhong;Shrestha, Chandra L.;Kopp, Benjamin T.
尽管在囊性纤维化（CF）治疗方案中加入了囊性纤维化跨膜传导调节因子（CFTR）调节剂，但CF患者仍持续遭受慢性细菌感染，导致进行性呼吸道疾病。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中起着不可或缺的作用。我们试图表征巨噬细胞对CFTR调节剂治疗的反应，因为我们假设基于患者基因型会有不同的影响。通过显微镜、流式细胞术和基于ELISA的测定分析人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、吞噬作用、细菌杀伤和细胞因子产生。与非CF MDM相比，CF MDM显示CFTR表达降低、细胞凋亡增加和吞噬作用降低。CFTR表达增加，细胞凋亡减少，响应ivacaftor或lumacaftor/ivacaftor治疗，吞噬作用改善与ivacaftor单独。依伐卡托恢复CF巨噬细胞极化反应至非CF水平，并降低铜绿假单胞菌细菌负荷，但不降低其他细菌负荷。巨噬细胞炎性细胞因子的产生减少，响应于单独的依伐卡托。总之，依伐卡托和鲁玛卡托/依伐卡托对巨噬细胞功能具有不同的影响，在用鲁玛卡托/依伐卡托治疗的CF患者中观察到最小的变化。依伐卡托治疗的CF患者中巨噬细胞功能的总体改善导致巨噬细胞介导的细菌杀伤适度改善。
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.