ORIGINAL RESEARCH article

Front. Immunol.

Sec. Molecular Innate Immunity

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1598306

MicroRNAs regulate alveolar macrophage homeostasis and its function in lung fibrosis

Provisionally accepted
Nirmal  ParajuliNirmal ParajuliYi  YaoYi YaoNamir  KhalasawiNamir KhalasawiCongcong  YinCongcong YinQiong  ZhangQiong ZhangIndra  AdriantoIndra AdriantoAakash  HansAakash HansLi  ZhouLi Zhou*Qing-Sheng  MiQing-Sheng Mi*
  • Henry Ford Health System, Detroit, United States

The final, formatted version of the article will be published soon.

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 monocytederived 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 miRNAdeficient 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.

Keywords: alveolar macrophage, microRNA, Pulmonary Fibrosis, epigenetics, Lung

Received: 22 Mar 2025; Accepted: 02 Jun 2025.

Copyright: © 2025 Parajuli, Yao, Khalasawi, Yin, Zhang, Adrianto, Hans, Zhou and Mi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Li Zhou, Henry Ford Health System, Detroit, United States
Qing-Sheng Mi, Henry Ford Health System, Detroit, United States

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