Fibroblasts as Protective Immunoregulators in Oral Mucosal Disease 2310061

Abstract Introduction The oral cavity is a critical barrier site that is continuously exposed to a variety of stimuli, including dietary components, the microbiome, environmental antigens, and mechanical stress and damage. Dysbiosis in this environment can lead to mucosal inflammation and subsequent alveolar bone destruction and tooth loss, a condition known as periodontitis. Our lab has previously highlighted the contribution of hematopoietic cells, especially Th17 cells and neutrophils, to the pathogenesis of periodontitis. However, insights from a human oral mucosal scRNA-seq atlas suggested that mesenchymal cells, including fibroblasts, may actively play a role during inflammation in the oral cavity.Based on this observation, we hypothesized that mesenchymal cells, particularly fibroblasts, contribute to oral mucosal pathogenesis. Methods Utilizing a mouse ligature-induced periodontitis (LIP) model which recaptures key features of human periodontitis, including dysbiosis, bone destruction, and immune cell infiltration, we performed time-course scRNA-seq to examine the transcriptome profile across different cell types in the oral mucosa during periodontitis development. Results Our analysis identified a subset of fibroblasts that became rapidly activated within 12 hours after ligature placement, exhibiting gene expression signatures associated with tissue inflammation and damage-related response, implicating the IL-33—ST2 signaling axis. The activated fibroblasts produced soluble ST2 (sST2), a decoy receptor for IL-33, early after the ligature placement. Functional studies in vivo using sST2 KO mice demonstrated sST2 KO mice significantly increased alveolar bone destruction compared to WT controls in the LIP model, indicating a protective role for sST2 in oral mucosal inflammation. Conclusion Overall, our work highlights the critical function of fibroblasts as immune-modulatory stromal cells that sense tissue stress and orchestrate inflammatory responses in the oral mucosa. Funding Source This project is funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research intramural program. Topic Categories Mucosal and Regional Immunology (MUC)