Abstract Rationale Iron homeostasis has been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. The transferrin receptor-1 (CD71), a key mediator of cellular iron uptake, is highly expressed on alveolar macrophages. In IPF, increased CD71-negative alveolar macrophages have been observed in bronchoalveolar lavage fluid, correlating with poor prognosis.1 However, the distribution of CD71 expression on peripheral immune cells in IPF has not been characterized. Methods Multiparametric flow cytometry was performed on peripheral blood from 26 IPF patients and 26 controls to assess CD71 expression across immune cell populations. CD71-positve and CD71-negative populations were quantified within CD45+ cells and within their respective lineages (T cells, monocytes, neutrophils, B cells, NK cells and granulocytes). Monocyte subsets were further evaluated in 12 IPF patients and 12 controls, classified as classical (CD14 ++CD16-), intermediate (CD14+CD16+), and non-classical (CD14-CD16 ++). Statistical comparisons were performed using unpaired T-tests, Mann-Whitney Tests, Wilcoxon signed-rank tests and Friedman’s test with Dunn’s post-hoc correction. Results IPF patients demonstrated a significantly lower proportion of CD71-negative T-cells relative to total T-cells (p = 0.0347), indicating a relative enrichment of CD71-positive T-cells, compared to controls. The distribution of monocyte subsets did not differ between IPF and control groups. However, CD71 expression varied significantly across monocyte subsets(Friedman p0.0001). Dunn’s post-hoc comparisons demonstrated that CD71-positive monocytes were predominantly classical(p = 0.0001), whereas CD71-negative monocytes were mainly non-classical(p = 0.0066). This pattern was consistent in both IPF and control groups with classical and intermediate monocytes containing significantly higher proportions of CD71-positive cells (p = 0.0005, p = 0.0015) and non-classical monocytes containing more CD71-negative cells (p = 0.0005). Conclusion These findings suggest that iron dysregulation in IPF extends beyond the alveolar compartment, influencing circulating T-cells and monocytes. The reduction in CD71-negative T-cells implies a shift towards an iron-hungry, metabolically active phenotype. Equally, higher CD71 expression within classical and intermediate monocytes suggests enhanced iron uptake and metabolic priming.Overall, these alterations highlight a systemic reprogramming of iron immuno-metabolism in IPF, linking disordered iron homeostasis to chronic immune activation and supporting iron metabolism as a potential therapeutic target in IPF. References 1. Allden SJ, Ogger PP, Ghai P, et al. The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2019;200(2):209-219. DOI: 10.1164/rccm.201809-1775OC. This abstract is funded by: None
Boyle et al. (Fri,) studied this question.