Endothelial Tgfß1 supports lung interstitial macrophage differentiation and pulmonary homeostasis

Lung interstitial macrophages (IMs) inhabit the lung parenchyma and are thought to contribute to lung immunoregulation and homeostasis. While recent progress has been made about the development, diversity and transcriptional regulation of lung IMs, the microenvironmental signals responsible for their tissue-specific identity remain unidentified. Here we found, in mice, that lung endothelial cell-derived Tgf 1 specifically triggered a core Tgf receptor-dependent lung IM signature in bone marrow-derived monocytes and macrophages (Macs). In vivo, myeloid-specific ablation of Tgf receptor signaling severely impaired monocyte-to-IM development, resulting in the accumulation of perivascular monocytes, decreased IM numbers and a severe loss of IM-intrinsic identity. Of note, monocyte-to-IM development was similarly impaired in the absence of endothelial-specific Tgf 1. Functionally, mice selectively lacking Tgf receptor in IMs exhibited a severe impairment of the lung immunoregulatory environment and prematurely developed lung hyperinflation, increased compliance and decreased elastance, changes classically associated with ageing. Our work identifies a novel endothelial - IM axis involving Tgf 1-Tgf r interactions that shapes IM identity and thereby sustains lung tissue integrity, thus providing foundations for IM-targeted interventions in the context of lung ageing and other chronic inflammatory disorders. Overall design: CD45.1/CD45.2 IMDTR mice were lethally irradiated with thorax protection and were fully reconstituted with BM cells either from CD45.2 Tgfbr2fl/fl mice or from CD45.2 Lyz2Cre Tgfbr2fl/fl mice. Four weeks later, chimeric IMDTR mice were treated with DT to specifically empty the IM niche and trigger IM niche refilling from either control or Tgfbr2-deficient monocytes. bulk RNA-seq was performed on reconstituted IMs 10 days after DT.