IL7-IL7R Interaction Mediates Fibroblast-Driven Macrophage-to-Osteoclast Differentiation in Periodontitis

To identify osteoclastogenic macrophage subsets and their regulatory mechanisms in periodontitis.

We integrated single-cell RNA sequencing datasets from human and murine periodontitis to construct a comprehensive macrophage and monocyte atlas. Employing functional enrichment, cell-cell communication, pseudotime, transcription factor, and machine learning analyses, we characterized and selected the specific macrophage subset involved in cell interactions. In vitro and in vivo experiments, including enzyme-linked immunosorbent assay, TRAP staining, micro-CT, qPCR, flow cytometry, and immunofluorescence staining, were performed to dissect the osteoclastogenic potential of specific macrophage subsets and to identify the key pathways.

We discovered that the IL7R⁺ macrophage subset possesses significant osteoclast differentiation potential. Our findings indicate that the IL7/IL7R signaling axis facilitates osteoclast differentiation. Genes highly expressed in IL7R⁺ macrophages were identified as strong predictors for periodontitis by machine learning models. In vivo and in vitro experimental validation confirmed an increase in IL7R⁺ macrophages, along with their enhanced osteoclastogenic capacity. confirmed an increase in IL7R⁺ macrophages, along with their osteoclastogenic capacity. The inhibition of the IL7/IL7R signaling pathway was found to mitigate periodontitis progression by impeding osteoclast differentiation. Furthermore, fibroblasts were found to secret IL7 interacting with IL7 receptors on macrophages.

Our study identifies IL7R⁺ macrophages as potential osteoclast precursors in periodontitis. We demonstrate that the IL7/IL7R signaling pathway is a critical driver of osteoclast differentiation. Moreover, targeting IL7R is a potential therapeutic strategy to curb periodontitis bone resorption.