Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro.
Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro.
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DOI：
10.3390/ijms22052530
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发表时间：
2021-03-03
影响因子：
5.6
通讯作者：
Tirouvanziam R
中科院分区：
文献类型：
--
作者：
Ford BD;Moncada Giraldo D;Margaroli C;Giacalone VD;Brown MR;Peng L;Tirouvanziam R
囊性纤维化（CF）肺部疾病主要是由骨髓细胞（中性粒细胞和单核细胞）从血液中募集，这些细胞不能清除肺部的定植微生物。在之前的体外研究中，我们发现血液中性粒细胞通过分化良好的肺上皮迁移到CF气道流体上清（ASN），模拟CF气道中性粒细胞在体内的功能障碍，包括尽管代谢增加，但杀菌活性降低。在这里，我们假设，以与中性粒细胞类似的方式，血液单核细胞在招募到CFASN时经历了显著的适应。为了验证这一假设，在我们的体外模型中，我们将健康对照（HC）或CF受试者的原代人血液单核细胞转移到ASN中，分别模拟正常或CF气道的体内募集。转运后，通过RNA测序对表面表型、代谢和细菌杀灭活性以及转录组谱进行了量化。与中性粒细胞不同，单核细胞没有代谢激活，与HCASN相比，它们在招募到CFASN时也没有表现出广泛的激活和清扫剂受体表达差异。然而，招募到CFASN的单核细胞杀菌活性下降。RNASeq分析显示，转运对单核细胞RNA谱有很强的影响，在CFASN和HCASN条件下存在差异，特别是在免疫信号方面，包括前者抗菌因子ISG15、防御素样趋化因子CXCL11和一氧化氮生成酶NOS3的表达较低。虽然单核细胞在招募到CF气道微环境时经历了与中性粒细胞在质量上不同的适应，但它们的杀菌活性也失调，这可以解释为什么它们也不能保护CF气道免受感染。
Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.
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影响因子：
7.3
作者：
Baharom F;Rankin G;Blomberg A;Smed-Sörensen A
通讯作者：
Smed-Sörensen A
DOI：
10.1016/j.jcf.2005.05.008
发表时间：
2005-08-01
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
--
作者：
de Winter-de Groot, Karin M;van der Ent, Cornelis K
通讯作者：
van der Ent, Cornelis K
影响因子：
5.2
作者：
Garratt, Luke W.;Wright, Adam K. A.;Sly, Peter D.
通讯作者：
Sly, Peter D.
影响因子：
4.4
作者：
Laval, Julie;Touhami, Jawida;Tirouvanziam, Rabindra
通讯作者：
Tirouvanziam, Rabindra
DOI：
10.1038/nrg3849
发表时间：
2015-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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