An ageing bone marrow exacerbates lung fibrosis via a dysregulated regulatory T cell driven axis, fuelling profibrotic macrophage persistence.

Pulmonary fibrosis is an incurable disease, which increasingly manifests with advanced age. Yet, how the ageing hematopoietic niche influences immune cell function and fibrosis progression in the lungs remains elusive. Using heterochronic transplant mouse models, we discovered that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased pulmonary infiltration of monocyte-derived alveolar macrophages (Mo-AMs) from an aged bone marrow. These Mo-AMs displayed an enhanced profibrotic profile and a delayed transition in acquiring a homeostatic tissue-resident phenotype. This impaired Mo-AM differentiation was attributed to diminished numbers of regulatory T cells (Tregs) and the reduced availability of the anti-inflammatory cytokine IL-10 in the lung microenvironment of mice engrafted with aged bone marrow. Mechanistically, we show that Tregs are crucial providers of IL-10 that promote timely Mo-AM maturation and attenuate fibrosis progression. Our findings demonstrate the critical influence of an aged bone marrow on the development of lung fibrosis and identify a Treg-mediated resolutory axis as a potential therapeutic target for accelerated tissue repair. To investigate the impact of hematopoietic ageing on lung immune cells during lung fibrosis, we transplanted young recipient mice with young or aged bone marrow. After reconstitution we challenged them with bleomycin intratracheally and sorted cells from the lungs (five cell types) at D7 and (two cell types) at D14 post challenge to analyse any gene expression/transcriptional differences between the recipient groups.