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Exploring the role of macrophage subsets in iron metabolism and their contribution to pulmonary fibrosis progression.

April 26, 2026

Distinct fibrosis-associated macrophage subsets coordinate iron metabolism in pulmonary fibrosis

Puntos clave

Exploring the role of macrophage subsets in iron metabolism and their contribution to pulmonary fibrosis progression.
Performed single-cell RNA sequencing on bronchoalveolar lavage fluid from patients with interstitial lung disease.
Conducted histological analysis to track macrophage population dynamics and their localization in lung tissue.
Identified increased accumulation of SPP1- and APOE-expressing macrophages in progressive pulmonary fibrosis and idiopathic pulmonary fibrosis.
SLC40A1+ macrophages mediated iron uptake and were linked to fibroblast transition to myofibroblasts, facilitating fibrosis.

Resumen

Pulmonary fibrosis has a poor prognosis due to challenges in early diagnosis and therapeutic intervention. Current treatments remain largely ineffective due to an incomplete understanding of the complex pathology, including the interactions between fibroblasts and profibrotic immune cells within fibrotic lungs. To elucidate the dynamics of fibrosis, we performed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) obtained from patients with interstitial lung disease (ILD). We identified the SPP1- and APOE-expressing macrophage population that is commonly present across ILDs. Histological analysis showed that this macrophage population accumulated at the center of fibrotic foci. Furthermore, the ratio of this macrophage population was increased in both progressive pulmonary fibrosis (PPF) and idiopathic pulmonary fibrosis (IPF). Transcriptomic analysis further divided this macrophage population into two subsets: SLC40A1+ or HAMP+ fibrosis-associated macrophages. We found that the relative balance of IL-10 and IL-8 regulated SLC40A1 and HAMP expression within fibrosis-associated macrophages. Additionally, histological analysis revealed that bronchial epithelium expressed IL-8, while type II alveolar epithelial cells expressed IL-10 in the fibrotic lung. SLC40A1+ fibrosis-associated macrophages localized to CD31+ perivascular regions and mediated the uptake and degradation of the hemoglobin-haptoglobin complex. This dual pathway-providing iron via SLC40A1 and intracellular iron accumulation via HAMP-facilitated the transition of fibroblasts into SPP1+ myofibroblasts. Moreover, ferroptotic fibroblasts secreted TGF-β1, which further contributes to fibrotic progression. In conclusion, aberrant iron metabolism orchestrated by fibrosis-associated macrophages may contribute to fibrosis by facilitating the transition of myofibroblasts. These findings provide mechanistic insight into the progression of autonomous pulmonary fibrosis.

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