The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis
The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis
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DOI：
10.1164/rccm.201809-1775oc
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发表时间：
2019-07-15
影响因子：
24.7
通讯作者：
Byrne, Adam J.
中科院分区：
文献类型：
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作者：
Allden, Sarah J.;Ogger, Patricia P.;Byrne, Adam J.
依据：特发性肺纤维化（IPF）是一种破坏性进展性疾病，治疗选择有限。气道巨噬细胞（AM）是气道防御的关键组成部分，与IPF的发病机制有关。在纤维化肺病和肺纤维化小鼠模型中，已经描述了铁代谢的改变。然而，转铁蛋白受体1（CD 71）表达的AM在IPF中的作用尚不清楚。目的：评估表达CD 71的AM在IPF肺中的作用。方法：我们使用多参数流式细胞术、基因表达分析和吞噬/转铁蛋白摄取测定来描述表达或缺乏CD 71的AM在IPF患者和健康对照受试者的BAL中的作用。测量和主要结果：与健康对照受试者相比，IPF患者中缺乏CD 71的AM比例明显增加。在IPF-BAL中，BAL转铁蛋白的浓度增加，此外，CD 71（-）AM隔离转铁蛋白的能力受损。CD 71（+）和CD 71（-）AM在表型、功能和转录上不同，CD 71（-）AM的特征是巨噬细胞成熟标志物表达减少、吞噬功能受损和促纤维化基因表达增强。重要的是，缺乏CD 71的AM的比例独立地与较差的生存率相关，强调了这一人群在IPF中的重要性，并作为一个潜在的治疗靶点。结论：总之，这些数据突出了CD 71如何划定AM亚群，在IPF中发挥不同的作用，并进一步表明，CD 71 AM可能是纤维化肺疾病的重要致病成分。
Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defense of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor 1 (CD71)-expressing AMs in IPF is not known.Objectives: To assess the role of CD71-expressing AMs in the IPF lung.Methods: We used multiparametric flow cytometry, gene expression analysis, and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing or lacking CD71 in the BAL of patients with IPF and of healthy control subjects.Measurements and Main Results: There was a distinct increase in proportions of AMs lacking CD71 in patients with IPF compared with healthy control subjects. Concentrations of BAL transferrin were enhanced in IPF-BAL, and furthermore, CD71(-) AMs had an impaired ability to sequester transferrin. CD71(+) and CD71(-) AMs were phenotypically, functionally, and transcriptionally distinct, with CD71(-) AMs characterized by reduced expression of markers of macrophage maturity, impaired phagocytosis, and enhanced expression of profibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target.Conclusions: Taken together, these data highlight how CD71 delineates AM subsets that play distinct roles in IPF and furthermore show that CD71 AMs may be an important pathogenic component of fibrotic lung disease.