Interplay between Porphyromonas gingivalis and EGF signaling in the regulation of CXCL14.

Porphyromonas gingivalis is a keystone pathogen in chronic periodontitis. Its expression of gingipain proteases (Kgp and RgpA/B) is central to the stimulation of chronic inflammation. In this study, we investigated the inflammatory response of oral epithelial cells to P.gingivalis. The cells responded by upregulating the expression of the orphan chemokine CXCL14. The stimulation of CXCL14 expression was largely triggered by the gingipain proteases and was dependent on the host protease-activated receptor PAR-3. Significantly, CXCL14 expression was transcriptionally repressed in response to epidermal growth factor (EGF)-induced activation of the MEK-ERK1/2 pathway. P.gingivalis overcomes the repression of CXCL14 via the gingipain protease-mediated degradation of EGF. Therefore, P.gingivalis not only directly stimulates CXCL14 expression via PAR-3 but also promotes its expression by antagonising EGF signalling. In addition to chemotactic activity, some chemokines also have antimicrobial activities. CXCL14 was demonstrated to have bactericidal activity, against commensal oral streptococci associated with health. Notably though, P.gingivalis was not susceptible to killing by CXCL14, potentially because the gingipain proteases can degrade CXCL14. This suggests that the stimulation of dysregulated CXCL14 expression by P.gingivalis may help promote dysbiosis and the development of chronic periodontitis.