Interleukin-7 receptor activation in interstitial macrophages promotes lung fibrosis through secreted phosphoprotein 1

RATIONALE: Osteopontin, also known as secreted phosphoprotein 1 (SPP1), is a critical mediator of lung fibrosis. However, the cellular sources of SPP1 and the mechanisms by which SPP1-producing cells promote fibrotic progression remain poorly defined. Objectives To define the functional roles and regulatory mechanisms of SPP1-producing macrophages in lung fibrosis. METHODS: Publicly available single-cell RNA sequencing datasets from patients with idiopathic pulmonary fibrosis were analyzed to investigate macrophage-fibroblast interactions. A bleomycin-induced lung fibrosis model was used in Spp1-enhanced green fluorescent protein (EGFP) knock-in reporter mice to identify Spp1-producing cells in vivo. Multi-omics approaches were applied to characterize profibrotic macrophage populations. The contribution of interleukin-7 receptor (IL7R)signaling in macrophages was evaluated using Il7r fl/fl Csf1r-iCre mice. MEASUREMENTS AND MAIN RESULTS: Single-cell transcriptomic analyses revealed fibrogenic interactions between SPP1-expressing macrophages and fibroblasts in human pulmonary fibrosis. In mice, interstitial macrophages (IMs) were identified as the predominant source of Spp1 in fibrotic lungs and promoted fibrosis by enhancing fibroblast activation. Spp1-EGFP + IMs expanded rapidly, peaking 7 days after bleomycin administration, and subsequently engrafted as inflammatory resident macrophages. Multi-omics analyses demonstrated that these cells produced glycoprotein non-metastatic melanoma protein B (Gpnmb), a profibrotic and proinflammatory mediator. SPP1-producing macrophages expressed IL7R in fibrotic lungs of both humans and mice. Macrophage-specific deletion of Il7r reduced Spp1 and Gpnmb expression and significantly attenuated lung fibrosis. CONCLUSIONS: SPP1-producing interstitial macrophages are key drivers of lung fibrosis through IL-7R-dependent mechanisms. Targeting the IL-7/macrophage/SPP1 axis may represent a promising therapeutic strategy for lung fibrosis.