Journal Article

MicroRNAs regulate alveolar macrophage homeostasis and its function in lung fibrosis

Yin, Congcong, Hans, Aakash, Zhou, Li, Zhang, Qiong, Khalasawi, Namir, Adrianto, Indra, Parajuli, Nirmal, Yao, Yi, Mi, Qing-Sheng

2025

Overview

Idiopathic pulmonary fibrosis is a progressive lung disease with a poor prognosis. Alveolar macrophages (AMs) are essential for maintaining lung homeostasis and play a significant role in the development of lung fibrosis. Tissue-Resident Alveolar Macrophages (TR-AMs), which originate from embryonic progenitors, can self-renew locally in a steady state, independent of hematopoiesis. During fibrogenesis, circulating monocytes rapidly migrate into the lungs and differentiate into monocyte-derived AMs (Mo-AMs). MicroRNAs (miRNAs), small non-coding RNAs, are critical for regulating gene expression. Our recent study found that the loss of miRNAs in embryonic progenitors significantly decreased the number of TR-AMs in late-stage embryos, indicating that miRNAs are necessary for TR-AM development. However, the role of miRNAs in the postnatal maintenance of TR-AMs and Mo-AMs, as well as their function in pulmonary fibrosis, remains unclear. Here, we demonstrate that deleting miRNAs after birth severely disrupts TR-AM homeostasis and Mo-AM repopulation from the bone marrow following irradiation. The deficiency of miRNAs in TR-AMs and Mo-AMs was linked to diminished bleomycin-induced experimental lung fibrosis. Mechanistically, the absence of miRNAs increased TR-AM apoptosis under both normal and fibrotic conditions. RNA sequencing (RNA-seq) analysis revealed distinct transcriptomic and pathway changes in miRNA-deficient AM subgroups after lung injury. The integration of RNA-seq and miRNA array analyses identified miRNA-mRNA networks in TR-AMs and Mo-AMs in response to bleomycin injury. Ingenuity Pathway Analysis further predicted let-7a, miR-155, and miR-125 as unique upstream regulators of Mo-AM responses to lung fibrosis. Our findings suggest that miRNAs are key epigenetic mediators that differentially regulate the maintenance and function of TR-AMs and Mo-AMs in the pathogenesis of pulmonary fibrosis.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: alveolar macrophage / Animals / Apoptosis / Bleomycin / Bone marrow / Cell growth / Disease Models, Animal / Embryogenesis / Epigenetics / Extracellular matrix / Fibrosis / Flow cytometry / Gene expression / Hemopoiesis / Homeostasis / Homeostasis - genetics / Idiopathic Pulmonary Fibrosis - genetics / Idiopathic Pulmonary Fibrosis - immunology / Idiopathic Pulmonary Fibrosis - pathology / Immunology / lung / Lung - metabolism / Lung - pathology / Lung diseases / Lungs / Macrophages / Macrophages, Alveolar - immunology / Macrophages, Alveolar - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / microRNA / MicroRNAs / MicroRNAs - genetics / miRNA / Monocytes / Postpartum period / Pulmonary fibrosis / Pulmonary Fibrosis - genetics / Pulmonary Fibrosis - pathology / Transcriptomics