Endothelial-driven TGFβ signaling supports lung interstitial macrophage development from monocytes.

Lung interstitial macrophages (IMs) are monocyte-derived parenchymal macrophages whose tissue-supportive functions remain unclear. Despite progress in understanding lung IM diversity and transcriptional regulation, the signals driving their development from monocytes and their functional specification remain unknown. Here, we found that lung endothelial cell-derived Tgfβ1 triggered a core Tgfβ receptor-dependent IM signature in mouse bone marrow-derived monocytes. Myeloid-specific impairment of Tgfβ receptor signaling severely disrupted monocyte-to-IM development, leading to the accumulation of perivascular immature monocytes, reduced IM numbers, and a loss of IM-intrinsic identity, a phenomenon similarly observed in the absence of endothelial-specific Tgfβ1. Mice lacking the Tgfβ receptor in monocytes and IMs exhibited altered monocyte and IM niche occupancy and hallmarks of aging including impaired immunoregulation, hyperinflation, and fibrosis. Our work identifies a Tgfβ signaling-dependent endothelial-IM axis that shapes IM development and sustains lung integrity, providing foundations for IM-targeted interventions in aging and chronic inflammation.