An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence
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 (T<sub>regs</sub>) 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 T<sub>reg</sub>-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.
Authors
- Riem Gawish (ORCID: https://orcid.org/0000-0003-4267-2131)
- А. А. Фокина (ORCID: https://orcid.org/0000-0001-5692-2483)
- Federica Quattrone (ORCID: https://orcid.org/0000-0001-5511-3000)
- Anna-Dorothea Gorki (ORCID: https://orcid.org/0000-0002-2521-0333)
- Florian Deckert (ORCID: https://orcid.org/0000-0002-3075-6808)
- Wilfried Ellmeier (ORCID: https://orcid.org/0000-0001-8192-8481)
- Philipp Starkl (ORCID: https://orcid.org/0000-0001-7521-129X)
- Lisabeth Pimenov (ORCID: https://orcid.org/0000-0002-5154-4070)
- Jörg Menche (ORCID: https://orcid.org/0000-0002-1583-6404)
- Louis Boon (ORCID: https://orcid.org/0000-0002-0937-9171)
- Felicitas Oberndorfer
- Karin Lakovits
- Joris van der Veeken (ORCID: https://orcid.org/0000-0001-7299-2174)
- Mariem Radhouani (ORCID: https://orcid.org/0000-0002-5739-9038)
- Sylvia Knapp (ORCID: https://orcid.org/0000-0001-9016-5244)
- Anna Hakobyan (ORCID: https://orcid.org/0000-0003-2667-6175)
- Cornelia Vesely (ORCID: https://orcid.org/0000-0003-2463-9223)
- Nicole Boucheron (ORCID: https://orcid.org/0000-0002-4979-8311)
- Asma Farhat (ORCID: https://orcid.org/0000-0003-4669-9438)
- Clarissa Campbell (ORCID: https://orcid.org/0000-0002-1918-0318)
- Sophie Zahalka (ORCID: https://orcid.org/0000-0003-0133-1672)
- Fanzhe Meng (ORCID: https://orcid.org/0000-0002-9820-1841)
- Anastasiya Hladik
- Jessica Brösamlen
Institutions
- University of Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- Max Perutz Labs (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Vienna Biocenter (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1126/sciimmunol.adk5041
- Citations
- 18
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 27.33