Gingipain-containing products from Porphyromonas gingivalis promote epithelial CCL20 signaling and γδ T-cell accumulation in COPD-like airways

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease in which impaired mucosal barrier function may increase susceptibility to aspirated oral microbial products. Periodontal disease has been associated with COPD development and exacerbation, but the epithelial mechanisms linking periodontal pathogens to pulmonary immune remodeling remain unclear. Here, we investigated whether gingipain-containing Porphyromonas gingivalis culture supernatant (PCS) promotes {gamma}{delta} T-cell-associated inflammation in COPD-like airways. Repeated intratracheal administration of PCS to {beta}ENaC-transgenic mice induced airway-centered immune cell accumulation and increased {gamma}{delta} TCR-positive cell accumulation, together with elevated expression of the {gamma}{delta} T-cell-associated cytokines Ifng and Il17a. PCS also increased pulmonary Ccl20 and Ccr6 expression, whereas epithelial alarmin-related genes and M2 macrophage-associated responses were not induced in parallel. In ENaC-overexpressing human airway epithelial cells, PCS induced CCL20 and F2RL1, the gene encoding protease-activated receptor 2 (PAR-2), and reduced the N-terminal PAR-2 signal, consistent with proteolytic receptor cleavage. Direct PAR-2 activation reproduced CCL20 induction, whereas pharmacological PAR-2 inhibition suppressed PCS-induced CCL20 expression. In contrast, PAR-1 inhibition or LPS neutralization with polymyxin B did not suppress this response. These findings support a mucosal epithelial protease-sensing model in which gingipain-containing P. gingivalis products activate PAR-2-dependent CCL20 production in airway epithelial cells and are associated with CCR6-linked {gamma}{delta} T-cell accumulation in COPD-like airways.