Interleukin-7 Receptor Activation in Interstitial Macrophages Promotes Lung Fibrosis through Spp1

Osteopontin, also known as secreted phosphoprotein 1 (Spp1), is a key molecule involved in lung fibrosis; however, the mechanism underlying the exacerbation caused by Spp1-producing cells remains unclear. In the present study, we investigated the detailed functions of Spp1-producing macrophages in lung fibrosis. Analysis of published single-cell RNA sequencing (scRNA-seq) datasets revealed the fibrogenic role of the interaction between <i>SPP1</i>-expressing macrophages and fibroblasts in patients with idiopathic pulmonary fibrosis. In addition, interstitial macrophages (IMs) were identified as the primary Spp1 source in the bleomycin-treated lungs of <i>Spp1</i>-enhanced green fluorescent protein (EGFP) knock-in reporter mice; their IMs promote lung fibrosis by enhancing fibroblast activation. <i>Spp1</i>-EGFP⁺ IMs expanded, peaking 7 days post-bleomycin administration and engrafting as inflammatory resident macrophages. Multi-omics analysis revealed that <i>Spp1</i>-EGFP⁺ IMs produced glycoprotein non-metastatic melanoma protein b (Gpnmb)-a fibrogenic, pro-inflammatory protein. Furthermore, Spp1-producing macrophages expressed the interleukin (IL)7 receptor on their surface in the fibrotic lungs of humans and mice. In the bleomycin-induced lung fibrosis model of Il7r^fl/fl Csf1r-iCre mice, macrophage expression of <i>Spp1</i> and <i>Gpnmb</i> was reduced, and lung fibrosis was attenuated, compared with those of Il7r^fl/fl mice. These profibrotic Spp1-producing macrophages and the IL-7/macrophage/Spp1 axis may represent therapeutic targets for lung fibrosis.