The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis

Abstract

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.

Macrophage metabolic reprogramming during chronic lung disease

“… ↓ Oxidative burst 141 ↓ Lipoxin A4 ↓ Anti-inflammatory potential 147 ↑ Acod11 Persistent P. Aeruginosa infection 143 ↓ CFTR-PTEN complex ROS production, succinate release 144 ↑ Iron ↑ ROS production 138 ↑ IRE-a pathway Increased glycolysis & Mt. function 149 IPF ↑ ROS Oxidative stress 175 ↑ Secreted Rac1 NOX, superoxide, mTOR activation 178 , 179 ↑ iNOS NO and OONO - production 181 , 182 ↓ HO-1 Loss of oxidative response 240 ↑ Iron uptake Oxidative stress & ROS 184 , 185 ↓ % of CD71 + AM Accumulation of transferrin 186 ↑ AKT Activation of HIF1α 241 ↑ GLUT-1, ↑ Glucose uptake NADPH production, superoxide 166 – 168 ↑ Glycolysis, glycolysis genes M2-like AM profile 166 ↑ FAO 166 ↑ MCU, ↑ Calcium, ↑ PGC-1α FAO reprogramming, mtROS TB ↑ ROS/RNS production …”

“…The proportion of AMs expressing transferrin receptor (CD71), importing transferrin bound iron into the cell, are decreased in IPF AMs, leading to an extracellular accumulation of transferrin. Furthermore, numbers of CD71-negative macrophages are an independent predictor of survival in IPF 186 . Iron metabolism is therefore likely a key pathway in IPF-AMs and targeting it would be a viable option to decrease ROS, oxidative stress and macrophage activation.…”

Dynamics of human monocytes and airway macrophages during healthy aging and after transplant

“…Collection of BAL samples BAL from healthy adult volunteers was obtained as previously described (Molyneaux et al, 2017;Allden et al, 2019). Briefly, bronchoscopies were performed under a light sedation with midazolam in combination with local anesthesia with lidocaine.…”

Influences of Nanoparticles Characteristics on the Cellular Responses: The Example of Iron Oxide and Macrophages

“…Concerning pulmonary diseases such as idiopathic pulmonary fibrosis (IPF), an impairment of the functionalities of macrophages, with an alteration of iron homeostasis in pulmonary fibrosis was observed. In this disease, alveolar macrophages are characterized by a deficient transferrin uptake, a reduced phagocytosis of S. aureus and an increase of NO production for unstimulated cells [60]. In such diseases, the functional effects observed on macrophages are linked to an overload in soluble iron.…”