囊性纤维化巨噬细胞中铁代谢的改变:CFTR 调节剂的影响及其对铜绿假单胞菌存活的意义。

Altered iron metabolism in cystic fibrosis macrophages: the impact of CFTR modulators and implications for Pseudomonas aeruginosa survival.

机构信息

Microbiology and Immunology, Dartmouth College, Hanover, NH, USA.

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 1 Medical Center Dr, Lebanon, NH, 03756, USA.

出版信息

Sci Rep. 2020 Jul 2;10(1):10935. doi: 10.1038/s41598-020-67729-5.

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in chronic bacterial lung infections and tissue damage. CF macrophages exhibit reduced bacterial killing and increased inflammatory signaling. Iron is elevated in the CF lung and is a critical nutrient for bacteria, including the common CF pathogen Pseudomonas aeruginosa (Pa). While macrophages are a key regulatory component of extracellular iron, iron metabolism has yet to be characterized in human CF macrophages. Secreted and total protein levels were analyzed in non-CF and F508del/F508del CF monocyte derived macrophages (MDMs) with and without clinically approved CFTR modulators ivacaftor/lumacaftor. CF macrophage transferrin receptor 1 (TfR1) was reduced with ivacaftor/lumacaftor treatment. When activated with LPS, CF macrophage expressed reduced ferroportin (Fpn). After the addition of exogenous iron, total iron was elevated in conditioned media from CF MDMs and reduced in conditioned media from ivacaftor/lumacaftor treated CF MDMs. Pa biofilm formation and viability were elevated in conditioned media from CF MDMs and biofilm formation was reduced in the presence of conditioned media from ivacaftor/lumacaftor treated CF MDMs. Defects in iron metabolism observed in this study may inform host-pathogen interactions between CF macrophages and Pa.

摘要

囊性纤维化 (CF) 是一种由 CF 跨膜电导调节因子 (CFTR) 基因突变引起的遗传疾病,导致慢性细菌肺部感染和组织损伤。CF 巨噬细胞表现出降低的细菌杀伤能力和增加的炎症信号。CF 肺中的铁含量升高,是包括常见 CF 病原体铜绿假单胞菌 (Pa) 在内的细菌的关键营养物质。虽然巨噬细胞是细胞外铁的关键调节成分,但铁代谢在人类 CF 巨噬细胞中尚未得到描述。在有无临床批准的 CFTR 调节剂 ivacaftor/lumacaftor 的情况下,分析了非 CF 和 F508del/F508del CF 单核细胞衍生巨噬细胞 (MDM) 的分泌蛋白和总蛋白水平。CF 巨噬细胞转铁蛋白受体 1 (TfR1) 在 ivacaftor/lumacaftor 治疗下减少。当用 LPS 激活时,CF 巨噬细胞表达的亚铁转运蛋白 (Fpn) 减少。在外源铁添加后,CF MDM 的条件培养基中的总铁含量升高,而经 ivacaftor/lumacaftor 处理的 CF MDM 的条件培养基中的总铁含量降低。CF MDM 的条件培养基中铜绿假单胞菌生物膜形成和活力升高,而 ivacaftor/lumacaftor 处理的 CF MDM 的条件培养基中生物膜形成减少。本研究中观察到的铁代谢缺陷可能会影响 CF 巨噬细胞与 Pa 之间的宿主-病原体相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1860/7331733/c2c160dd6f7d/41598_2020_67729_Fig1_HTML.jpg

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