ICAM1+ gingival fibroblasts modulate periodontal inflammation to mitigate bone loss

Tissue-resident fibroblasts are heterogeneous and provide an endogenous source of cytokines that regulate immunologic events in many osteolytic diseases. Identifying distinct inflammatory fibroblast subsets and conducting mechanistic <i>in vivo</i> studies are critical for understanding disease pathogenesis and precision therapeutics, which is poorly explored in periodontitis. Here, we surveyed published single-cell datasets for fibroblast-specific analysis and show that Intercellular Adhesion Molecule-1 (ICAM1) expression selectively defines a fibroblast subset that exhibits an inflammatory transcriptional profile associated with nuclear factor-κB (NF-κB) pathway. ICAM1⁺ fibroblasts expand in both human periodontitis and murine ligature-induced periodontitis model, which have upregulated expression of CCL2 and CXCL1 compared to other fibroblast populations. Using a mouse model to selectively target gingival stromal cells, we further show that disruption of an inflammatory pathway by inhibiting transcriptional activity of NF-κB in these cells accelerated periodontal bone loss. Mechanistically, this was linked to a reduction of CCL2 expression by the ICAM1⁺ fibroblasts, leading to impaired macrophage recruitment and efferocytosis that was associated with persistent neutrophilic inflammation. These results may have a significant therapeutic implication as ICAM1⁺ gingival fibroblasts exert a protective response by regulating innate immune responses that are needed for the controlled inflammatory events in early stages of periodontitis.