Dual-tissue single-cell analysis reveals a shared interferon-stimulated gene program and a predominantly non-neuronal trigeminal response in experimental periodontitis.

Periodontitis destroys the tooth-supporting tissues, yet whether a local periodontal lesion is accompanied by changes in the distal trigeminal sensory system at cell-type resolution is poorly defined. In ligature-induced periodontitis (male mice), we profiled the gingiva by single-cell and the trigeminal ganglion (TG) by single-nucleus RNA sequencing, integrating gene-set enrichment, regulon (SCENIC), communication (CellChat) and ligand-target (NicheNet) analyses with micro-computed tomography and histology, and tested the principal findings in individual mice by RT-qPCR (n = 8 per group) and immunofluorescence (n = 6 per group). Micro-CT and histology confirmed alveolar bone loss and osteoclast activity. Gingival cell-type composition shifted toward immune cells, whereas that of the TG changed only modestly. Descriptively, an interferon-stimulated gene (ISG) program with increased activity of ISGF3 regulons was enriched across nearly all cell types of both tissues. In individual mice, Isg15, Ifit3 and Oasl2 increased 4.7- to 9.3-fold in the gingiva and 3.4- to 3.9-fold in the TG. In the TG, ISG15-positive TUBULINβ3-negative non-neuronal cells rose from 8% to 67% of nucleated cells, whereas sensory neurons showed only a small ISG shift; a subset retained IFNAR expression. Ligand-target inference nominated gingival interferon ligands as candidate upstream regulators of the trigeminal ISG program. These data describe an interferon/ISG-associated program at the lesion and in the distal ganglion, consistent with type-I signaling in the gingiva; its interferon class in the ganglion, source, route and functional consequences remain to be established.