Periodontitis, a pervasive chronic oral inflammatory condition, poses substantial public health and economic burdens (Hajishengallis & Chavakis, 2021). As highlighted by the Global Burden of Disease 2016 study, severe periodontitis ranks as the 11th most prevalent global condition, impacting over half of the world's population (Vos et al., 2017). This disease not only affects oral health but is also epidemiologically linked to an array of systemic maladies, including cardiovascular disease, type 2 diabetes mellitus, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, nonalcoholic fatty liver disease, and certain forms of cancer (Atarashi et al., 2017, Genco and Sanz, 2020, Hajishengallis and Chavakis, 2021, Kitamoto et al., 2020, White and Sears, 2023). Recent developments in periodontal research have deepened our understanding of periodontitis’ role in both local and systemic pathogenic effects, primarily mediated by inflammation-driven pathways (Atarashi et al., 2017, Chavakis et al., 2022, Kitamoto et al., 2020). A key component in this process is the cytokine interleukin 17 A (IL-17A) signaling (Dutzan et al., 2018, Veldhoen, 2017, Zenobia and Hajishengallis, 2015).

The dual nature of mucosal IL-17A, its protective and detrimental impacts, is a focal point in mucosal barrier studies (Amatya et al., 2018, Dutzan et al., 2017, Gaffen and Moutsopoulos, 2020). IL-17A is predominantly produced by type 17 immune cells, including T helper 17 cells, CD8 + T cells, γδ T cells, natural killer T cells, and innate lymphoid-like cells (Mills, 2023). The detrimental role of IL-17A in gingival inflammation, characterized by its contribution to bone loss and tissue degradation in periodontal disease, is well-established (Eskan et al., 2012, Moutsopoulos et al., 2014). Yet, the barrier-protective role of IL-17A is less understood. IL-17A’s signaling through interleukin 17 receptor A (IL-17RA) is typically confined to nonhematopoietic cells, notably epithelial cells. IL-17A/IL-17RA signaling on oral epithelial cells is instrumental in antifungal immunity (Conti et al., 2009, Conti et al., 2016, Aggor et al., 2020). In the context of periodontitis, IL-17RA mediates host defense against Porphyromonas gingivalis-induced bone loss by defective neutrophil recruitment to the gingival epithelium (J. J. Yu et al., 2007). Moreover, clinical evidence suggests that periodontitis may be a more critical factor than smoking in the induction of marginal gingival thickness (Gültekin et al., 2008). Increased epithelial thickness is often regarded as a response to inflammation thus mediating mucosal homeostasis (Naik & Fuchs, 2022). However, the direct link between IL-17A and oral epithelial cell proliferation has been insufficiently explored.

We hypothesized that type 17 immune response plays a pivotal role in maintaining the oral epithelial barrier by facilitating the proliferation of oral epithelial cells in periodontitis. In our research, we investigated type 17 immune response in the ligature induced periodontitis model. Our findings demonstrate that IL-17A triggers the proliferation of human normal oral keratinocytes, evidenced by the activation of phosphorylated signal transducer and activator of transcription (p-STAT3), Yes-associated protein (YAP), and c-JUN. Importantly, in the ligature induced periodontitis model, this proliferative activation extends beyond the gingival region to the adjacent tongue epithelium, revealing an extensive oral epithelial cell proliferative response. Notably, targeting IL-17A in ligature induced periodontitis markedly diminishes this proliferative activity in oral epithelial cells, accompanied by downregulation of p-STAT3, YAP, and c-JUN.