An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence

Sci Immunol. 2025 Mar 28;10(105):eadk5041. doi: 10.1126/sciimmunol.adk5041. Epub 2025 Mar 28.

Abstract

Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (Tregs) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies Treg-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging* / immunology
  • Animals
  • Bone Marrow Transplantation
  • Bone Marrow* / immunology
  • Bone Marrow* / pathology
  • Female
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Lung / immunology
  • Lung / pathology
  • Macrophages, Alveolar* / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Fibrosis* / immunology
  • Pulmonary Fibrosis* / pathology
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Interleukin-10
  • IL10 protein, mouse