[Periodontitis: epithelial cells-fibroblasts pathological reprogramming and inflammatory memory]

Gingival epithelial cells and fibroblasts maintain oral mucosal homeostasis. In periodontitis, these cells undergo pathological reprogramming to drive chronic inflammation and tissue destruction. This review outlines the mechanisms underlying this transformation. Epithelial barrier disruption initiates inflammation, activating gingival fibroblasts via epithelial-derived extracellular vesicles, microbial engagement, and cytokines. These gingival fibroblasts differentiate into pro-inflammatory gingival fibroblasts such as those highly expressing serum amyloid A1 and those with a senescence-associated secretory phenotype. Cellular senescence, its associated secretory phenotype and epigenetic modifications synergistically stabilize these pathological phenotypes. Reprogrammed cells, including epithelial cells undergoing epithelial-mesenchymal transition and fibroblasts with a senescence-associated secretory phenotype, ultimately drive extracellular matrix degradation and alveolar bone resorption by overproducing matrix metalloproteinases and upregulating receptor activator of NF-κB ligand. Targeting pro-inflammatory gingival fibroblasts subpopulations may offer precision interventions for periodontitis.